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a lot of people put all their items on esau and leave jacob alone which helps synergies snowball harder but remember you get diminishing returns from repeated stat upgrades so depending on your situation it might be better to split the upgrades or cram them on one guy. Pills are great as them, one makes you larger doesnt increase your hitbox size yet one makes you smaller reduces your hitbox size. i prefer to put all the hitbox size down on one guy so i can be pseudo-one player, the current hitbox size downs in the game are caffeine pill, binky, one makes you smaller, mini mush, and pluto. Other than that its just a lot of being able to make split-second minute adjustments to make sure j&e are sticking together, which requires a bit of practice. I personally prefer having jacob and esau side by side instead of having one on top of the other but i dont know how much of a different it makes.
Don't put all your eggs in one basket, give stat ups to the brother with the lower number every time. Though if you get flying for one or both of them, balancing stats doesn't matter nearly as much. They both share the speed stat too.
Consider giving one of them red health priority and the other soul/bone/black heart priority and giving the Negative to the latter. The free room damage on every hit when a character has no red health has always been really strong and it's a damage up to boot.
Items and pills that reduce size make them much more playable too. Less colliding with each other and the environment makes dodging easier.
Personally, I always go angel with them. Both because they're frail af so the red/temp health downs from devil deals are often a death sentence, but also because it gives me a shot at Mega Satan in a best case scenario.
J&E are by far my least favourite non-tainted character, but they do have a lot of flexibility in ways that no other character does. Just keep a level head and knock the completion marks out one at a time if you have to.
It's pretty much playing the game like you have Isaac's heart from the start, except the heart can also get items and doesn't make you invincible. Just takes a bit of practice and you'll have to accept you won't win as many runs as you might with other characters