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So yeah, hevily depends whether you're lucky or not, but it doesn't require any skill to finish
Pitch Black: Hagalaz, easy, save for later (do ASAP in Repentance)
High Brow: Jera, pretty easy, do ASAP
Head Trauma: Ehwaz, rather challenging, save for later (do ASAP in Repentance)
Darkness Falls: Dagaz, easy, save for later (do ASAP in Repentance)
The Tank: Ansuz, pretty easy, on the fence (do ASAP in Repentance)
Solar System: Perthro, rather challenging, do ASAP
Suicide King: Suicide King, hard, save for much later
Cat Got Your Tongue: Algiz, rather challenging, do soon (do ASAP in Repentance)
Demo Man: Chaos Card, easy, do ASAP
Cursed!: Credit Card, pretty easy, do ASAP
Glass Cannon: Rules Card, easy, save for much later
When Life Gives You Lemons: The Card Against Humanity, pretty easy, save for later (can be used to completely trivialise Ultra Greed but rather unhelpful otherwise)
Beans!: Burnt Penny, very hard, do ASAP (unless you don't use bombs often)
It's In The Cards: SMB Super Fan, rather easy, on the fence (not a good item, not a bad item)
Slow Roll: Swallowed Penny, stupidly easy, do ASAP (practically required to play as one of the secret characters)
Computer Savvy: Robo Baby 2.0, stupidly easy, on the fence (not good, not bad)
Waka Waka: Death's Touch, rather challenging, do ASAP
The Host: Tech.5, pretty easy, do ASAP
The Family Man: Epic Fetus, very hard, DO AS SOON AS UNLOCKED
Purist: Berkano, pretty challenging, save for later (do ASAP in Repentance)
XXXXXXXXL: Gold Hearts, pretty easy, do soon
SPEED!: Get Out of Jail Free Card: very hard, do ASAP
Blue Bomber: Gold Bombs, hard, do ASAP
PAY TO PLAY: Percs + Addicted pills, pretty easy, save for later
Have a Heart: Re-Lax + ??? pills, pretty easy, save for much later
I RULE!: Poker Chip, easy, save for later
BRAINS!: Stud Finder, very hard, save for later
PRIDE DAY!: D8, pretty easy, save for later
Onan's Streak: Kidney Stone, rather challenging, do ASAP
The Guardian: Blank Rune, very hard, save for later (do ASAP in Repentance)
Backasswards: Lazarus starts with Anemic and Lazarus Risen gets permanent Anemic, pretty easy, do ASAP
Aprils Fool: Magdalene starts with a Speed Up pill, pretty easy (especially if you've unlocked Gold Hearts), do ASAP
Pokey Mans: Keys sometimes recharge your active item, pretty challenging, do soon
Ultra Hard: Samson starts with Child's Heart, very hard, save for much later
Pong: Greed's Gullet, very easy, do ASAP
Scat Man: Dirty Mind, very easy, save for later
Bloody Mary: Sigil of Baphomet, very hard, do ASAP
Baptism By Fire: Purgatory, relatively easy, do ASAP (note: you will need about 24 charges to beat Isaac, and the jar only stores 20, try not to reach Isaac without any bonus Soul Heart charges left)
Isaac's Awakening: Spirit Sword, relatively easy, DO AS SOON AS UNLOCKED
Seeing Double: Broken Glasses, hard, do ASAP
Pica Run: Ice Cube, relatively easy, do ASAP
Hot Potato: Reverse Chariot Card, hard, do ASAP
Cantripped!: Reverse Justice Card, incredibly easy, do ASAP
Red Redemption: Reverse Hermit Card, relatively easy, do ASAP
DELETE THIS: Reverse Temperance Card, incredibly annoying, get it out of the way if you like Pills (it's all fun and games until the passive item you just picked up gives you infinite Swords of Damocles)
Dunno if you can say this is the hardest. It's just rng based which doesn't really have anything to do with difficulty. It took me about 7 runs until I got an item let me control enemies which made it a walk through challenge. Ultra hard and the like on the other hand...
Suicide king drives me up the wall too. I think it's my last base game challenge left.