The Binding of Isaac: Repentance is the latest expansion for the iconic roguelike, and to say it brings some seismic changes is an understatement. The mod-turned-official-DLC has upended Isaac's meta through nerfs, buffs, and other alterations that have proven contentious among the community thus far.
Time-honored strategies have been taken away, resources occur at a different frequency, hard mode is hard for everyone again. It's a lot, so here are the biggest changes you should know about.
Shops and Devil Deals are less effective
Two of the more reliable spots for players to acquire powerful pickups during a run have been significantly altered. Neither shops nor the sacrificial Devil Deals are as likely to supply that game-changing weapon, nor can you break them quite as easily.
Shops are the bigger deal. Three alterations are imperative: Items that appear once aren't likely to reappear again, having two Steam Sales does not reduce the prices to zero, and reduced prices otherwise won't happen if you're using Steam Sale.
If you find a great attack boost in an early-game shop, but don't have the pennies for it, it's unlikely to be available again later. The Steam Sales nerf is a more reactive change to a known exploit. A Steam Sale reduces shop prices by 50 percent, and it used to stack, meaning a second gave you 100 percent off. Combine this with restock, which automatically replaces any item bought in a shop with another, and you can just keep picking stuff until you're an unstoppable monster.
Also, restocks bring items back with an increased price, so you'll still need money. Developer Edmund McMillen has been actively working on balancing this post-release, but the point stands: Nothing's for free in Repentance.
Devil Deals, however, are just less likely to give you anything crucial. The item pool has been diluted, to the point where there won't always be something worth the heart cost—Devil Deals are like shops, but they take health points instead of money (unless you get A Pound of Flesh, switching the two currencies.)
One of the characters, The Lost, can't farm the Devil's items either. Previously, they could take every item in a Devil Room, now the others disappear after you pickup one. Making a deal with the dark lord just isn't what it used to be, eh?
Hard Mode is still hard
This sounds trite, but the higher difficulties in The Binding of Isaac: Repentance have been calibrated to make sure seasoned players have a tough time. The last full expansion, Afterbirth+, launched in 2015, so now many in the community know every likely difficulty spike. Repentance makes some effort to throw those preconceptions out of the window.
Enemies are faster, and getting those S-tier synergies is now considerably tougher. That said, this has been tweaked since release. The first patch upped the frequency of max-level shops and tinted rocks appearing, thus granting better access to those killer items, and increased the chance of heart drops during grueling runs.
Your favourite combo probably doesn't work any more
The real nitty-gritty of The Binding of Isaac: Repentance is in its weapons changes. The list on release was long, and it sought to challenge fixed approaches. Some fan-favourite components are just gone, like Polyphemus, which increased damage and made shots go through enemies they killed. Others have been tweaked to prevent certain game-defining powers, such as Tammy's Head, a powerup that fired tears in ten directions, no longer gives Brimstone a damage bonus. You still get your full room blood coverage, it's just not quite as lethal.
You can still find worthwhile synergies, of course, they're just not likely to make for easy runs like before. For example, I use Jacob's Ladder to electrify all my tears so damage is chained between nearby enemies, and a demonic pickup that builds my rage-per-enemy killed to turn me into a rainbow-colored fiend that damaged any enemies I touched. I ended up dying in Depths II, because as good as this was, I still lost control of later rooms.
That's the important part to remember: Repentance takes some control out of your hands. Rather than finding a seed that has Tech X and the appropriate boosters so you can clear every room by sending out wave after wave of electricity, you're going to have to think carefully about how you use that weapon, because its damage is now scaled.
Another combo I enjoyed was Brother Bobby and Cube Baby, wherein I shot tears at two different targets while kicking a giant frozen baby their way to freeze them. Simple, but extremely effective. You're very unlikely to find anything like Dark Bum—a familiar who supplies set items based on hearts you picked up that now delivers based on random draw rather than on a cycle—to assist you in a routine fashion.
Same goes for Humbling Bundle, where previously bombs and hearts and so on became their doubled version—now you only have a chance of that happening. In some cases, combos have just been switched. Proptosis used to make Maw of the Void's ring larger, now it stays the same size, but Ipecac now blows enemies up on contact. It's give and take, and you need to always be open to the possibilities, rather than thinking of getting a certain kind.
It's hard to give definitive advice right now, and that's part of the point. The best thing you can do for yourself with The Binding of Isaac: Repentance is just start playing and see what happens. Just don't ignore Cube Baby.