Dear god Mom is obnoxious... but easy to deal with if you have the right combo (which happens one in a million times...). The Headless Horseman and pestilence are two very interesting bosses as well, what with their charge thing and all, while Famine and the Lord of Flies are just too easy and generally drop worthless things. Now, I know there are more than 13 endings to this game (many darker than others), but the symbolism of going into the womb and the coat hanger (when you put them together) is just too creepy...
On of my friends doesn't take evil items or make deals with the devil. His loss, really, since some of the best items can be bought that way... and also, who doesn't want to look like a freakin' demon, right?