For me, the toughest battles (in difficult order) were:
1 - The Twisted Rune (I couldn't even escape the fight because the room was so narrow and small and the door was locked)!
2 - Firkraag. Exactly when I thought Nalia had hilled him with 2 cloudkills and 1 death fog, he cast heal on himself and I had to confront him with non-area effect spells...fire protection spells had a short duration...ans as this wasn't enough, my party had to defend itself from his physical attacks...
3 - Kangaxx the Demi-Lich. Few weapons that could hurt him. Hard to hit and virtually immune to magic...and imprisonment spells
4 - The Mind Flayers'lair in Underdark. As someone has pointed out, it's not a very difficult battle but you have a fight every inch you come across. Just one mistake and you're dead.
5 - And finally, the final battle with Slayer/Irenicus. Not because of the slayer himself, but because of that bunch of demons - protection from evil had no effect!!!