The Binding of Isaac: Rebirth

I'm really surprised at how good Chocolate Milk is now. In the original I never even picked the item up because it was that bad.
I just had a run that started out with Chocolate Milk + Piercing Shots + Pentagram (XL Floor) and it ended up going all the way through to Mega Satan (lol, Dad's Key opens Mega Satan's door) and I'm pretty sure Chocolate Milk is what carried me through. Although I was able to pick up Scythes and some other decent damage ups along the way so of course those helped as well.

I also discovered God Rooms are now twice as good as they were in the original since you can kill the angels and then reroll the key pieces into other god items. Although this means missing out on the Mega Satan fight, in most cases.