It would be fascinating to take a peek inside of Edmund McMillen's mind, as the quirkiness of his first co-developed hit, Super Meat Boy, doesn't completely foreshadow the extreme (and somewhat glorious) infantile silliness of The Binding of Isaac, his second big hit (also co-developed). The game references Christianity in a very loose way that is sacrilegious to be sure, but so far removed from the source material that it's fairly inoffensive. Similarly, the game is also full of satanic references and scatological humor and fairly gory violence, but it's all so cartoony that it's entertaining rather than really disturbing.
The game is a roguelike that plays a lot like the 2D dungeons in the original Zelda games with the twin-stick shooting mechanics of games like Smash TV (in this game, the eponymous Isaac's tears serve as bullets). It's evolved from its humble Flash beginnings in 2011 and has been released in its "Rebirth" incarnation on all modern platforms. I played the Switch version, which includes all of the original's DLC, and apparently for Nintendo fans there are also 3DS and Wii U versions. The game is chock-full of items, although it's annoying that the game doesn't give you much information about how they work (although there are plenty of resources such as wikis to help you out online). Its level of difficulty is "old school" hard, but you can replay the same "seed" over and over again until you beat it rather than generating a different configuration every time. As with all roguelikes, because of the random generation some seeds are definitely going to be harder than others, and even the easier ones will take a fair amount of effort to beat. A large part of the game is learning enemies' behaviors and bosses' patterns, so your acccrued experience with the game does benefit you over time.
The game's extras take the form of daily challenges, unlockable characters with different abilities or handicaps, and extra floors with even harder bosses to challenge once you defeat "Mom", the first main boss. I started off not really liking the game much at first, but I got to like it much more as I got used to the mechanics and its unique aesthetics. It's kind of annoying having to look up the effects of everything, and a lot of them seem overly situational (i.e. not useful at all for a particular seed), but there's much more variety with the items than I had first expected. Because of the huge catalogue of items, there is a good amount of variety with the random generation, and a lot of replayability. I was happy to play a few seeds and move on, but I can see why fans return to the game over and over again. In the end I did have to tip my hat to the game and add it to my "greatest games of all time" for its unique personality, solid gameplay, and at times overwhelming number and variety of items. Not sure when I'll pick it up again, but it was definitely a memorable experience.