Gannondorf, Legend of Zelda Ocarina of Time.
-Lethal Tennis, a full-demonic transformation and fighting him with your Weapon knocked away
Death, Castlevania (Series)
-Fighting Death himself...pretty damn Epic
Elite Four then Champion, Pokemon Red/Blue
-Fighting these five for the first time is a real RPG slog, but certanly satisfying
Dark Samus, Metroid Prime 3 Corruption
-Fighting a Dark Version of yourself is pretty amazing, especially when its mutated into this massive beast which is poisionous to touch: Homing Missles at the Ready!
I'll add some more when I think of some more
EDIT:
Minerva, Final Fantasy Crisis Core
-The sheer feat of getting to battle Minerva is challenge enough, but fighting her is a completly different matter, she has a massive "10000000" HP, and fantasticly mountinous stats elsewhere also. She has a 99'999 Ultima which even if you block it, it deals 64,583 damage!