Running shoes, my friend. Running shoes. I beat him 15 levels lower than by brother, at level 45.
OK, hardest boss ever. Hmm...
Megaman 7's Dr. Wily, second form. His attacks were *this* close to being undodgeable, and a full charge shot inflicted a single damage on him, if you could hit him at all.
Honorable mentions:
Angband: Morgoth. 20,000 HP when you never really do much more than 600 damage per round. His regular attack causes small, localized earthquakes.
ADOM: Andor Drakon. Invisible, stat draining, insta-kill, summoning, you name it. Death by courruption. Praying for divine intervention, which normally heals you in that game, instead summons hordes of Greater Balors. Almost impossible.
Zande from ff3j. The first time, my battle went like this:
Round 1: He scans us.
Round 2: Meteo. We all die.
Zeromus in the japanese version of ff4. Just big and bad and tough.