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.
Want to surpass even that? Ipecac plus Epic Fetus plus a damage multiplier of at least 1.5 (Cricket's Head, Magic Mushroom, Eve's Mascara, and a few others). To make it even crazier, add Inner Eye or Mutant Spider to have multiple missiles fire down.
Let's just say that any time you manage to put together a nasty combination of items to tear apart your enemies on a single run is one of these.
A bit of a meta example, but on its 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. The expansion, Afterbirth, provides a special meta example in how it doesn't supplant Mega Satan as the True Final Boss, making this the first major update or expansion that does not add a new True Final Boss and defy precedent. Instead, we get a Bonus Boss and an alternate mode with its own Final Boss.
Another meta example: former Nintendo of America head of indie relations, Dan Adelman, was thanked by the developers as the reason for Rebirth seeing release on the Nintendo eShop after the game's initial rejection in 2012. Adelman himself once stated that one of his regrets from his days at Nintendo was being forced to reject Binding of Isaac's initial 3DS release, due to Nintendo's eShop content guildlines still being outdated and restrictive at the time. Thanks to some reforms Adelman was able to work out at Nintendo prior to leaving and starting his own company, Binding of Isaac was, at long last, able to see release on Nintendo platforms in 2015 in the form of the Rebirth version.
Defeating Isaac as the Blue Baby and unlocking the D6. An awesome item in its own right, this item lets the user re-roll any item pedestal in the room. Don't like it? Re-roll it! But what makes unlocking it all the more awesome is that it immediately becomes Isaac's starting item by default. This turns Isaac from a basic, mediocre, but well-rounded character into the closest thing you can get to a wild card without playing as Eden.
One interpretation of Ending 15 turns it into this for Isaac. After being trapped with his abusive mother for who knows how long, he makes the choice to finally run away from home. It might be hard out there, but almost anything is a better option than living with the crazed woman who thinks God wants her to sacrifice her only son.