I think someone should make a list of the "must-have" unlockable items.
I'm bored at work, so why not... I'm using the
wiki's achievement list order, so I'm not listing by best unlocks or anything. I'm guessing you're trying to get at the "best unlocks" that will save runs for you, but there aren't really any of those aside from Stopwatch. These are all items that are useful to have in the item pool and worth going for the unlock for, either because they're always useful in every run or because they can be lifesavers in the right situation. Some of them are things you probably already unlocked but since I don't know what you have, I'll just list all my favorites.
Book of Revelations (Gives a soul heart but forces you to fight a horseman)
Noose (Flight)
Quarter (Money! Good because it can show up in pots and skulls)
Dr Fetus (Weaker than in the original but still a fun item)
Small Rock (Damage up)
Bandage (HP up, soul hearts)
Relic (Soul heart every 5 rooms)
Little Gish (Slowing tears)
Halo (All stats up)
Mr Mega (Bomb blast radius and damage)
D6 (Rerolls)
Parasite (Split shots)
Mom's Contact (Freezing tears)
Mom's Knife (Win the game)
Guardian Angel (Better orbitals)
Demon Baby (OK orbital)
Forget Me Now (Rerolls the floor)
D20 (Rerolls consumables)
Celtic Cross (Shield when hit, high chance to proc)
Curved Horn (Damage up, only trinket that does so)
Blue Candle (Attack item)
Epic Fetus (Win the game again)
Maggy's Faith (Eternal heart on every floor)
Judas' Tongue (All devil deals cost 1 heart)
The Left Hand (All chests are red)
Jera (Doubles all consumables in the room, including chests)
Perthro (One-time reroll)
Chaos Card (Instakill any enemy, including any boss)
Credit Card (All items in a shop or devil room are free)
Death's Touch (Damage up, changes your tears to badass scythes)
Technology .5 (Gives you a third eye that fires tech laser)
Eve's Mascara (Damage up, though with rather severe rate of fire and shot speed downgrades)
Fate (Flight)
???'s Only Friend (A familiar that works like Ludovico Technique)
Store Credit (One free store item)
Pandora's Box (Gives a random drop of a bunch of flies, an item or 2-4 soul hearts)
Blank Card (Allows you copy the card you're holding infinitely)
Undefined (Teleports you to special rooms)
Satanic Bible (Gives black hearts, doesn't seem to be any drawback)
Abaddon (Damage up at the cost of all red hearts)
The Mind/The Body/The Soul (Full map reveal/3 red hearts/3 soul hearts + enemy projectiles dodge you)
Blue Map (Secret room reveal)
There's Options (Every boss drops 2 items)
Black Candle (Curse immunity + 1 black heart)
Red Candle (Attack item)
Stopwatch (Slows every enemy in every room for the rest of the game, yes you read that right)
Wire Coat Hanger (Rate of fire up)
Ipecac (Win the game if you can aim)
Blood Bag (HP up)
Godhead (Massive tears upgrade in almost every way, like Sacred Heart)