Just some things you should focus on unlocking as well as things you shouldn’t.
Why Should You Trust Me?
I’ve been playing and watching Isaac for over half a decade at this point. I came from PS4 and moved to PC, and I have over 600 hours of experience playing TBoI between them. Most importantly, I got Dead God without any gameplay-altering mods, so I’ve personally done all of these unlocks already.
TLDR: I’m a really good and experienced player.
The Good Ones (Part 1)
I’ll start off with the ones you can get earlier on and work my way towards the later-game unlocks towards the end.
Broken Modem (Complete seven daily challenges) & Cracked Crown (Complete five daily challenges in a row, they don’t have to be consecutive days)
Broken Modem is my favorite item in the entire game since its awesome buff. Whenever you pick up this item you are guaranteed to think to yourself “Thank you, Broken Modem!” at least once during your run because of the numerous beneficial things it does. Because daily challenges are completely separate from the rest of the game in terms of unlocks, you have no reason to not play a daily challenge every day until you unlock Broken Modem. While you’re at it, try to get Cracked Crown as well; it’s a really good stat trinket.
Azazel (Take three Devil Deals in a single run)
You’ll probably unlock him without actually trying to but I figured I’d mention him anyway. In my opinion, Azazel is the single most powerful character in the game. He is the character you’ll normally want to use for non-character specific unlocks because of how powerful he is, and he is also required to unlock Satanic Bible.
Ace of Clubs (Win three times in a row)
You might get this one without trying but just in case you should try to do this one as soon as you unlock Azazel as the game is going to get harder the longer you play it. Ace of Clubs is a pretty good card that can wipe a difficult room and give you a bunch of bombs.
Jera (Complete Challenge #2: High Brow)
Despite its nerf this is still one of the best usable pickups in the game. The challenge is also really easy.
Chaos Card (Complete Challenge #9: Demo Man)
This card single-handedly trivializes many difficult bosses in the game. It will come in as a run-saver for you many times. The challenge itself is pretty easy.
Mom’s Knife (Defeat Satan with Isaac)
This is one of the most powerful tear replacement items in the game. It melts bosses and will win you runs.
Satanic Bible (Defeat Isaac with Azazel)
On top of being a run-winning health item that increases your odds of making deals, Satanic Bible works well with The Lost and Tainted Lost, unlike Book of Revelations.
Blood Bag (Use health donation machines 30 times)
If you’re playing the game correctly you should unlock this one without trying. On top of giving you a health up, it restores four hearts (can refill the health you just donated) and augments your speed. Also, did you know that using Spindown Dice on Blood Bag turns it into Brimstone?
Store Upgrade Level 1 (Donate 20 coins to the donation machine)
Having a larger shop is going to benefit you greatly later on and the cost isn’t that much all things considered.
Blank Card (Defeat Isaac with Eden)
It got nerfed pretty hard in Repentance. You can still break the game with it, though, and it has a pretty easy unlock condition.
Lucky Pennies (Donate two coins to the Greed Mode donation machine)
Outside of beating Greed Mode to begin with the barrier of entry to this very good unlock is very low. Do this while getting the next unlock.
Lilith (Beat Greed or Greedier! Mode with Azazel)
Lilith is necessary to unlock Incubus, C Section, and Twisted Pair, all of which are on this list.
The D6 (Defeat Isaac with ???)
On top of being a direct upgrade for Isaac, this is one of the best active items in the game for any character that will improve the quality of your other items.
Forget Me Now (Defeat Satan with ???)
A very solid item with a reasonably easy unlock condition, Forget Me Now also synergizes extremely well with ‘M.
The Void (Defeat Hush)
Unlocking The Void as possible is going to save you a lot of hassle later on for annoying Delirium unlocks due to the mercurial nature of the portal appearing or not. You’re going to need to defeat Delirium to get list-inhabitants Eden’s Soul and D Infinity.
Incubus (Defeat Hush with Lilith)
Incubus is an incredibly powerful item that, in essence, doubles the amount of tears you put out with no downside aside from whatever cost you paid to get it. Make this your first Hush unlock.
D Infinity (Defeat Delirium with Isaac)
This is the best dice item in the game. Its versatility is simply unmatched. 100% a run-winner that you should prioritize unlocking as soon as you defeat Hush.
Eden’s Soul (Defeat Delirium with Eden)
This is a lot of people’s favorite 12 charge active item and for good reason. It gives you two items from whatever item pool you’re currently occupying, which is incredibly strong for an active item. Did I mention it synergizes very well with ‘M?
Downpour (Defeat Hush three times)
You’re gonna need this to get to Mother.
The Good Ones (Part 2)
Strange Door & Jacob & Esau (Defeat Mother)
The Strange Door is, in my opinion, the single most important unlock in the game. It opens the way to the game’s final ending, so if you’re just trying to “beat” the game it will be your last unlock before you do that. It’s also required to unlock every tainted character in the game, many of which have S tier unlocks. Jacob & Esau allow you to unlock The Stairway and Birthright. You can get this unlock while doing the next one.
‘M (Defeat Mother with Eden)
Fun fact: I believe this was my last (or at least close to last) normal character Mother unlock. I massively underestimated this trinket. Don’t be like me. This is definitely one of the best trinkets in the game and can turn a bad active item into an extremely powerful one out of the blue, like an R Key. On top of that, you can just drop it when you’re satisfied and don’t want to reroll anymore. Make this your first Mother unlock.
The Polaroid (Defeat Isaac five times)
Necessary to access Chest, which opens the way to all ??? unlocks, including Birthright and Blessed Penny. You should probably prioritize unlocking The Polaroid over The Negative, since Chest is an easier floor to complete than Dark Room.
The Negative (Defeat Satan five times)
Necessary to access Dark Room, which opens the way to all The Lamb unlocks, including Missing Poster, Curved Horn, The Soul, and Damocles.
Curved Horn (Defeat The Lamb with Judas)
This is one of the best trinkets in the game. Its simple damage up is incredibly powerful.
Bethany (Defeat Mom’s Heart on Hard mode with Lazarus without dying)
Bethany is necessary to unlock Book of Virtues, Blessed Penny, and Revelation.
Book of Virtues (Defeat Isaac with Bethany)
Book of Virtues is a great active/passive item that improves (almost) every active item you’ll get for the rest of your run.
Blessed Penny (Defeat ??? with Bethany)
This is probably the best coin trinket in the game that makes coins much more useful from Chapter 4 forward.
Revelation (Defeat Mother with Bethany)
I found this unlock to be difficult but it is well worth it. Revelation is a four-headed beast that gives you flight, two soul hearts, and the ability to fire a powerful holy laser. On top of all that, it also contributes to the Seraphim transformation.
The Stairway (Defeat Isaac with Jacob & Esau)
Absolutely one of the best angel room items in the game that can be a definite run-winner. This will give you tons of angel room items for the rest of the run and can also enable you to get both key pieces. Get this unlock while doing the next one.
Birthright (Defeat ??? with Jacob & Esau)
Definitely one of the best items in the game hands down because of how personalized it is. This item will be a huge boon for your run for 33/34 characters and can save your run. I will admit Jacob & Esau are not the easiest characters but these are probably their two easiest unlocks and they also happen to be the characters’ best ones.
Tainted Lilith (Enter the secret closet with Lilith)
Tainted Lilith is needed to unlock Twisted Pair, so you’re gonna want her. Do this unlock while getting the next one.
C Section (Defeat The Beast with Lilith)
One of the best items in the game and probably the best tear replacement. C Section is going to win you many runs pretty much by itself and should definitely be your first unlock from defeating The Beast.
Twisted Pair (Defeat The Beast with Tainted Lilith)
Just gonna say it right here: Tainted Lilith is a very easy character and I would hope nobody disagrees with me on this one. To this effect, unlock Twisted Pair immediately after unlocking Tainted Lilith. It is basically a better Incubus that heavily ameliorates the devil deal pool and its trivial unlock condition makes it a no-brainer.
Tainted Isaac (Enter the secret closet with Isaac)
Just gonna say it right here: 5/6 of Tainted Isaac’s unlocks are great and one of them even makes this list, so you should make this your second tainted character unlock. Do this unlock while getting the next one.
Options? (Defeat The Beast with Isaac)
This item is heavily underrated. It basically fixes any need for pickups by itself. It also synergizes well with Broken Modem, which you either have unlocked by now or are close to unlocking. I will admit, though, this item is really only on this list because you can get it right after unlocking Tainted Isaac, so if you end up losing to Dogma or The Beast after entering the secret closet it’s not a priority to go back for Options?.
Glitched Crown (Defeat The Beast with Tainted Isaac)
Once you get used to this item, it undoubtedly becomes a run-winner. Glitched Crown is absolutely one of the best unlocks in the game that is, in essence, The D6 on steroids.
Tainted Lazarus (Enter the secret closet with Lazarus)
Tainted Lazarus is necessary to unlock Flip.
Tainted Azazel (Enter the secret closet with Azazel)
Tainted Azazel is one of the most powerful characters in the game that will make your Greed mode grind easier. Lil Abaddon is an aggressively mediocre item but it’s not going to harm your save file that much to unlock it afterwards.
Tainted Judas (Enter the secret closet with Judas)
Like the last unlock, Tainted Judas is one of the most powerful characters in the game that will make your Greed mode grind easier. Redemption is an inoffensive item that you will barely see after unlocking it if you manage to defeat The Beast.
The D20 (Defeat ??? with Isaac)
The D20 is a fairly good item in its own right, but it allows you to break the game in Greed and Greedier! mode. Notwithstanding, you should put off unlocking this item until you’re planning to grind out the Greed donation machine, since Isaac’s Tears, a terrible item, is also required to be unlocked to get The D20, and is, in my opinion, a net negative for Normal and Hard mode.
Holy Mantle & Keeper (Donate 879 and 1000 coins respectively to the Greed donation machine)
This is an annoying achievement. Use Tainted Cain, Azazel, Tainted Lilith, Cain, Tainted Judas, Lilith, Tainted Magdalene, Isaac, and Tainted Azazel to get it. Don’t just use one of these characters as the chance for the Greed donation machine to break permanently increases for the character you’re playing whenever you donate to it. Once you unlock Holy Mantle, which is an incredible item in its own right and borderline required for The Lost, you can choose to move to the next unlocks and come back later or just finish it off. And for the record, if you cheat here I’m gonna be really disappointed in you.
Missing Poster (Defeat The Lamb with Isaac)
This trinket is required to unlock The Lost.
The Lost (Die in a self-sacrifice room while holding Missing Poster)
You’re going to have to throw away a run in order to do this. Unless you’re actively going for it, it’s not gonna be a good feeling. Make sure you don’t get teleported to Dark Room when your last heart is depleted. I speak from personal experience when I say that it will not unlock The Lost.
Damocles (Defeat The Lamb with Jacob & Esau)
To be clear, this item is pretty bad for most characters in the game. But for characters that can’t take damage anyway, it is very strong.
The Soul (Defeat The Lamb with The Lost)
This is a little tricky to unlock but this item is really going to help you out for some of the hardest bosses in the game.
Tainted Lost (Enter the secret closet with The Lost)
Tainted Lost is unfortunately necessary to unlock Sacred Orb.
The Good Ones (Part 3)
Keeper’s Wooden Nickel (Defeat Isaac with Keeper)
This makes all other Keeper unlocks much easier.
[Optional] Keeper’s Penny (Defeat Hush with Keeper)
This makes the rest of Keeper’s unlocks easier but not as much as Wooden Nickel does. This unlock is very challenging. If you’re struggling to get the next two unlocks I recommend you go for this one first, but if you can get them without it then it’s definitely not a priority.
Keeper’s Sack (Defeat Mother with Keeper)
Difficult unlock, fantastic item. Keeper’s Sack is guaranteed to improve any run tenfold.
Tainted Keeper (Enter the secret closet with Keeper)
Tainted Keeper makes filling up the regular donation machine easier if you haven’t done that already. He is also necessary to unlock Golden Pennies.
Stop Watch (Donate 999 coins to the donation machine)
Like most items on this list, this is one of the best items in the game that not only makes everything slower but also makes you faster. Its unlock condition is kind of a pain in the ass but it’s worth doing, especially because a lot of the unlocks in-between are very useful as well. Use Tainted Keeper, it will make the entire ordeal much easier. Make sure you don’t donate over 999 cents to the donation machine, though, as that will instantly empty it out and prevent you from using it as a bank for future runs.
Apollyon (Defeat Mega Satan)
Apollyon is necessary to unlock Echo Chamber. Do this while getting the next unlock.
Golden Pennies (Defeat Mega Satan with Tainted Keeper)
This wasn’t that hard for me to accomplish but it might be more difficult for you, so you might want to unlock some more coin-based items before attempting this. Golden Pennies are important to have, though, as they synergize very well with coin trinkets and are in general a strong strict upgrade.
Tainted Apollyon (Enter the secret closet with Apollyon)
Tainted Apollyon is necessary to unlock Echo Chamber.
Echo Chamber (Defeat The Beast with Tainted Apollyon)
Despite its nerf, Echo Chamber is still a juggernaut. This is a great item to have for any run and allows you to break the game.
Flip (Defeat Delirium with Tainted Lazarus)
This unlock can be very difficult, which is why it’s towards the end of this list. Notwithstanding, Flip is an incredible and highly underrated item that functions as an alternative Damocles.
Sacred Orb (Defeat The Beast with Tainted Lost)
Fantastic item that buffs your run considerably by improving the quality of items you get. Miserably difficult unlock condition. This should definitely be done after most of the others.
The rest of these unlocks are challenge-based that you can do whenever you feel as though you’re strong enough. They are direct and strong buffs to the game that have virtually no downsides.
Gold Heart (Complete Challenge #21: XXXXXXXXL)
Gold Bomb (Complete Challenge #23: Blue Bomber)
Charged Key (Complete Challenge #33: Pokey Mans)
The Bad Ones
I probably won’t order these like the good ones. This is just a general list of the worst unlocks in the game that you should try to put off for as long as possible.
Missing No. (Complete Boss Rush with Lazarus)
This is the worst item in the game. It has zero redeeming qualities and basically ruins any run where you have it. You have to actively go out of your way to get it, so make sure you put this awful item off for as long as possibly and only unlock it when you’re planning on getting Mega Mush or Death Certificate.
Torn Card (Defeat Mother with Tainted Lazarus)
This trinket is so bad. It knows exactly how bad it is, too. Do yourself a favor and don’t add stupid My Reflection Ipecac tears to your run.
Scissors (Die 100 times)
Ultimately, this unlock is inevitable, but because of how insufferably bad Scissors is you should try to avoid dying just so it’s not added to your game.
Samson’s Child’s Heart (Complete Challenge #34: Ultra Hard)
The unlock from this challenge isn’t worth the pain and boredom at all. Ultra Hard is the hardest and worst challenge in the entire game and by the time you beat it you’ll like the game less and feel much less motivated to get the rest of the unlocks. Samson is an easy character and you don’t need Child’s Heart to fill out his completion marks, so put off doing this mortifying challenge for as long as possible.
TMTRAINER (Defeat The Beast with Tainted Eden) & Corrupted Data (Defeat Delirium with Tainted Eden)
Two horrible unlocks for a horrible character. Not only are these difficult to get, but they add “glitch” items to your game, which are entirely unpredictable and can easily ruin your run after taking them. Glitch items are bad, keep them out of your game.
IBS (Defeat Delirium with Tainted ???)
This item just gets in the way and really isn’t good at all. Its unlock condition sucks, too.
Suicide King (Complete Challenge #7: Suicide King)
Suicide King literally kills you. It is only good if you are playing as Lazarus, and by the time you unlock it you will probably have all his unlocks done anyway because he’s an easy character. Normally trashing an extra life just isn’t worth it. The challenge is asinine and obnoxious, too. Avoid this.
Rules Card (Complete Challenge #11: Glass Cannon)
If you are the type of person that is willing to read this guide then you have essentially exhausted any sort of usefulness that Rules Card can provide. All this card does besides that is take up a spot in the card pool that could’ve been a Joker or Chaos Card.
Re-Lax/??? (Complete Challenge #25: Have a Heart)
One of these pills is stupid and the other is REALLY bad and designed to troll you with its name. This challenge is not worth doing unless you’re trying to 100% the game.
Abel (Defeat The Lamb with Cain)
This item is infamous for how bad it is. They even tried to buff it in Repentance but it still sucks. Do yourself a favor and put off unlocking it.
Sticky Nickels (Complete Boss Rush with Keeper)
If someone asked me why I think bad unlocks are the worst thing about Isaac, this is the one I’d show them. The epitome of the asinine unlock, Sticky Nickels are supposed to replace pennies, which would’ve made it at least subjectively an upgrade. But instead, it replaces normal nickels, so it is an objective downgrade. The only time this unlock would be useful is if you’re doing a no coin pickups challenge and you accidentally walked over it. “That was a close one! I almost collected a coin!”
Shade (Defeat Delirium with Judas)
This item wouldn’t be so egregious except for the fact that it occupies the Devil Deal item pool, meaning that there’s a chance it can replace a much better item like Incubus or Brimstone. It can also replace a Guppy item in a red chest, which I don’t think I need to elaborate on as to why that’s abysmal. Unless you’re playing Tainted Magdalene, avoid unlocking this.
Isaac’s Head (Complete Boss Rush with Isaac)
Mid trinket, fairly easy unlock condition. Wait on unlocking this item.
The High Priestess? (Complete Greedier! mode with Tainted Lilith)
You remember how difficult it was unlocking The Forgotten? This card lets you relive that for a minute, and that’s all it does. Just bad.
Wheel of Fortune? (Complete Greedier! mode with Tainted Cain)
It wouldn’t be that terrible if it was just D4 as a card, but this card basically acts like a single use D Infinity except you’re spamming the drop button without looking at the icon. Does that sound good to you?
Soul of Judas (Complete Boss Rush and defeat Hush with Tainted Judas)
This item makes no sense. Tainted Judas can do this every few seconds for free, so why put that power into an item that takes up a card slot and also clutters the rune pool? It’s not that the rune does anything bad, per se, but like the Rules Card it hardly does anything good.
Berkano (Complete Challenge #20: Purist)
This item is kinda useful for one room. If you’re wondering why this is here, there’s another rune with an even easier challenge that not only gives you a soul heart but can get rid of Curse of the Blind.
???’s Only Friend (Complete Boss Rush with ???)
It’s just horribly weak and a chore to take advantage of. Why would you prioritize unlocking this?
Hushy (Defeat Hush as Apollyon)
Not only is Hushy awful, but had there been a lack of creative bankruptcy amongst the dev team it could’ve even been cool.