I love TBOI, it's one of my fave games on steam, but holy crap it's hard. Either that or I'm just completely useless xD
When I first got it, the Wrath of the Lamb DLC bundle was on offer, so I jumped straight in with that. I think that was the mistake. Some of the monsters from the DLC I struggle with, mainly the spiders. I know they're supposed to be easy, you find them on the first floor for crying out loud, but their movement is too erratic I usually end up not realising one is headed straight at me till it does some damage.
I also struggle more with some of the early bosses too. With the exception of maybe the first two, every time I've made it as far as mom, I've beaten her, but some of the earlier bosses are capable of killing me every time I get to them.
I've already pre bought Rebirth, can't wait till it comes out. Hopefully I'll be better at that than I am at the original xD