The End is the obvious answer. Until you figure out how to defeat him, he's gotta be the most frustrating boss. Admittedly someone told me about the controller switch in MGS1 so I didn't have to deal with Psycho Mantis's BS. Vamp/Screaming Mantis were probably intended to be the same level of "WTF wat do I do?" but they really weren't, maybe I was just smarter, or it was just more obvious, but their weakness came to me pretty quick. The hardest boss once you know how to beat them? Probably Colonel Ocelot (NOT Revolve Ocelot from MGS1, he's a joke). Going straight pistol to pistol is awful on Extreme. Fight made me wish the game had MGS4 aiming. Raging Raven is probably #2, and Chrysalis is probably #3.