Original Syndicate comes quite close too. That last mission, with 2 - 3 full squads of cyber agents on each platform, must've been about 10 - 12 platforms, and basically all of them with line-of-sight to where your squad had to go... got it done eventually but I remember stressing over that mission for some time!
In the top 10 list, Crawmerax the Invincible from Borderlands 1 is truly epic!! After the DLC with the claptrap ninja, with the addition of 10 more levels you can gain, I figured by gaining some more levels (got to about 67 with 69 being the new max lvl) and going back to Crawmerax at a higher level (he was lvl60 or 61 before the DLC if I recall correctly) perhaps he can be beaten, but noooooo - he is now level 70 and as epic as ever!!! One does not simply kill Crawmerax... I gave up.
If anyone has done this before or have any tips, or want to join on steam and help, please notify me via PM. I hate leaving games unfinished like this.
Out of this World on the Amiga was insanely hard. They've released an android version, but playing one of the most difficult games from my youth on a multitouch surface is not my idea of a good time...
I really struggled in Homeworld 2. Think I got up to the 3rd level. Also Black and White 1, the mission where the meteors kept falling down was really tough.
Ask anyone who has played Vanquish about the infamous "Challenge 6" and they will probably give you a b!tch slap. Basically if you blink during the challenge you will get owned.