First thing that comes to mind? My first ever master difficultly playthrough. Zero magic resistance. A high elf named Orchendor. Much blood shed and gnashing of teeth.
I've probably fought harder battles since, but that one stands out in my mind at the minute.
On edit: Sorry, I didn't realise this wasn't a Skyrim thread. In that case, I'll have to give it some thought. One I recall being a right pain in the backside was the end boss from the first Gears Of War, especially on higher difficulties. An absolute bitch to kill... and not in an enjoyable way either. It was as tedious as it was frustrating.
N64 classic. Toilet humour - pun intended - is the order of the day. This is the great mighty poo singing his battle anthem.