Oh, I got another one. SPOILERS FOR INFINITE SPACE!!!
The Overlords. As soon as humanity has populated enough of space they come and bring the death of the ENTIRE Universe completely and to bring it back into one point to create another universe and they generally treat the universe as a plaything to expirement with. Not as a massive one either, they treat it like a child does with a chemistry set.
Hell, the only way to have stopped them is by destroying their transportaion from their universe to ours... the only damn way possible! They can also tear planets apart in a minute! Kinda scary in game.