(see other people's choices here
And here's the obligatory Neal Adams cover. ;) His work combines meticulous draftsmanship with an eye for dramatic composition, and his covers always command attention. Here we have a classic cliffhanger: A battered and helpless Batman, about to be thrown to his death. The massive figure of the bad guy dominates the scene. He's scary and formidable, rippling with muscles as he hunches over the defeated hero. There's no elaborate death-trap or intellectual puzzle involved here... this guy just beat the crap out of Batman, and is about to finish him off! Adams' artwork announced to the world that the tv-influenced "camp" era was over, and Batman was now Serious Business.
This one has personal significance... it's the first Batman comic I ever remember owning. The interior art by Novick and Giordano is pretty sweet too.