Final Fantasy X. Evrae, Seymour Flux and Overdrive Sin can all hand your your arse if you don't know they're there in advance and don't train beforehand. In the case of the International/PAL versions, the Dark Aeons can destroy you before you even get a turn if you haven't spent a LOT of time training.
Borderlands. Mothrakk. The quest says it's level 21, given the difficulty of "Trivial". Okay then, no problem. I drove straight there, summon him and he turns out to be level 25. I can't do any damage, while he throws two fireballs at me, bringing my vehicle to about 15 health and forcing me to bail out. He then bombards me with fireballs, killing me before I can get a second sniper shot off. I wasn't pleased.
God of War 2. Theseus on Titan. He has an attack where he summons icicles from the floor that cover an eighth of the area, and touching a single icicle kills you instantly. Not once did I die by any other means during that fight and I counted how many tries it took me. I died 42 times.
Gears of War. RAAM on Insane. I HAD to use the bug where he get stuck behind the concrete block to beat him. The best part was, he even killed me with his Troika one time while he was stuck and I was behind cover.
Turok (2008). The Beast. He has an attack where he rips two stalactites from the ceiling and throws them at you, one after the other. Getting hit by one drains half your health, and if you roll too early, he anticipates this and throws it right at you, hitting you every time. If your health is low enough, he can eat you for an instakill. You also have to kill him by igniting a gas vent in the ground at the right time with a flamethrower about twelve to fifteen times. Did I mention that this was on Normal difficulty, and there are two difficulty levels above that?