The game is reminiscent of the 8- and 16-bit Zeldas in its mechanics, enemy design and level design, although dungeons are made up of never-the-same-twice rooms and the whole thing is draped in a nightmarish basement aesthetic loosely inspired by an ancient story about child sacrifice.
Its fictional premise is unique compared to most games and the intro cinematic was certainly entertaining, if a little overt in its Biblical themes, but I sense that it takes the Shadow of the Colossus / Metroid approach of using cinematic sequences to merely bookend the lengthy action part of the story. That is to say it opens with a 'premise cinematic', lets you spend a very long time doing stuff in response to that premise and closes, when you reach your goal, with a 'job done cinematic'. I may well be wrong (please correct me if I am), but that's how it appears from the demo. It's an effective enough structure (and has been touched upon here) but does leave the bookends feeling like exposition overkill when the rest of the game's narrative is delivered so sparingly.
For all its flaws (which I tend to dwell on when I deconstruct a game) Isaac is a shining example of a top-end indie game which demonstrates a strong understanding of the challenges presented by overhead camera angles in 2D games.
It's dirt-cheap on Steam (with soundtrack available too) and the free demo is playable in your browser on Newgrounds.