Not at all the hardest game, but one of the hardest (i.e. frustrating) parts I've ever played was in ME2 on insanity difficulty. When you try to save all the colonists on Horizon (I think that's the name). It wasn't so bad if you imported a character, but if you started a play through from scratch it was a mother-blam!-er. That and Grissom Academy were the two toughest parts of the game