Getting Brimstone and Polyphemus. All of the non-final bosses go down in either 1 or 2 hits. The two final bosses, Isaac and ???, which have 2000 hp, go down in 5 or 6 hits. It makes you feel like a god.
A bit of a meta example, but on it's release day, Rebirth topped Steam's sales charts, surpassing Call of Duty: Advanced Warfare. To make that even more awesome, Steam's sales charts are based off of gross revenue. Considering Rebirth is only one fourth of Advanced Warfare's price...
Rebirth's boss rush, AKA every boss up to the Depths (as well as Blastocyst and Death) from the original Binding of Isaac and WoTL, teaming up to take you down. Bonus points to Isaac and the player if they manage to survive the horde.
And Rebirth's True Final Boss, Mega Satan, a massive version of Satan that attacks with Bullet Hell, slamming his Giant Hands of Doom, and summoning the Horsemen of the Apocalypse, the Seven Super Deadly Sins, and two fallen versions of the Angel minibosses. And that's not getting into his second form...
Beating a run on Rebirthas The Lost. Especially if you beat Mega Satan with it. Give yourself a pat on the back; after what you've went through, you've earned it.
Meta: The sheer amount of content. First, the Halloween free update. Then the Wrath of the Lamb expansion, which was two-thirds of the original game. Then Rebirth raised the item count to +340 from the original's 100 or so of. And as of this writing, there's a Rebirth expansion in the works that will double the amount of content.