The end boss in Fracture was dissapointingly annoying.
As well, I got annoyed with the Hunter in the 360's Prince of Persia. You can only throw him off a cliff and hope for the best.
Army of Two had the stupid jerk who killed my pilot, left the cock-pit and tried to kill the two main chars. What was his frakkin end-game?!?! There is no way on the Goddesses green Hyrule that he would survive the crash that my guys barely survived last minute. NO WAY. Then he comes back and I have to kill him.... AGAIN.
In Turning Point: Fall of Liberty, the false president nazi turn-coat took too many hits for a lazy puppet fat guy.
Rainbow Six: Vegas 2, there was the helicopter at the end.
Finally (For what I can think of off the top of my head at least), we have the Butterfly boss from Dark Cloud 2 (Might be Dark Chronicle for some of you). Shoot this color, then this color, then this color, and if you auto-target accidently to this color out of order, you fail, and need to start over. Yarggh.