It would have to either be the Insane Cancers SH3 or the ghosts in SH4. The ghosts are not only a pain in the ass, but they can't be dodged all that easily, either.

The Insane Cancers are just huge and the don't really back up much when you shoot or hit them. On top of that, they've got loads of health and it seems to take them forever to finally go down. Bastards...

The more and more I see SH2, the more and more I want to play it....right freakin now! It's on it's way, so I won't have to wait too much longer.