The hardest acheivement that I've gone for and succeeded at in recent memory was the Medal Seeker achievement in Dead Block. It required four gold medals on every level, and the only way you can get gold is by playing on hard. The medals were for destroying and searching through all the objects (of which there were MANY), killing a certain number of zombies per level, and not dying. The hardest medal to get was for not dying, and it was pretty much impossible to get all four medals at once, so I would break it up.
I'm having a really hard time with an achievement I'm trying to get right now. I'm playing L.A. Noire and there's an achievement worth 80 points for completing all the cases with a 5-star rating. You can't miss many clues or get many questions wrong without impacting the star-rating, so I'm having to go back and replay a lot of the cases to up my rating.