Even just unlocking it counts as an awesome moment in and of itself, as this requires beating every main boss in the game with the Lost, and if you installed any of the DLCs, you have to beat their bosses with said character as well. When picked up, it gives Isaac homing tears with a huge damaging aura around them that straight-up melts most enemies. Especially if you beat a hard final boss such as DELIRIUM or THE BEAST.
Beating any run as The Lost - both versions if you are playing Repentance. And that's not getting into his second form. 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. Bonus points to Isaac and the player if they manage to survive the horde. 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. Considering Rebirth is only one fourth of Advanced Warfare's price. 
To make that even more awesome, Steam's sales charts are based off of gross revenue.
A bit of a meta example, but on its release day, Rebirth topped Steam's sales charts, surpassing Call of Duty: Advanced Warfare. 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. 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. An awesome item in its own right, this item lets the user re-roll any item pedestal in the room. Defeating Isaac as the Blue Baby and unlocking the D6. Compare the latter to Head of Krampus, which takes six rooms to recharge and only fires four beams in the cardinal directions. And Tammy's Head? Once every room, you get to fire ten beams all at once in different directions, pretty much cutting through any non-final boss and shredding any enemy that cannot make itself invulnerable. Spoon Bender turns the beam a nice violet color and has it curve around to hit what few enemies might avoid it. Tiny Planet, normally a Scrappy Weapon, changes Brimstone so that you get a "shield" of it of sorts before it fires straight ahead anyway, with no downsides. 20/20 (from Afterbirth onwards), Inner Eye, and Mutant Spider let you fire two, three, and four Brimstone waves at once respectively, and if you're lucky enough to get more than one of these items or clone them with Diplopia/Crooked Penny, they add up (for a maximum of 16). 
Not only that, but the number of synergies with this relatively rare, unique (not counting Mega Blast of Afterbirth or that Azazel starts with a short-ranged version of it) item is impressive.
You know those annoying blood-lasers that many mid-to-late-run enemies and some of the most infamous bosses fire at you? A general That One Attack for the whole game with limitless range that passes over obstacles to hit you? The signature move from bosses such as the Bloat and the Adversary? This gives you the power to fire them on your own.
Brimstone by itself is an incredible item. 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. To make it even crazier, add Inner Eye or Mutant Spider to have multiple missiles fire down. THE BINDING ISAAC BINDING OF ISAAC DIPLOPIA PLUS
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).Want to surpass that? Both Technologies and Ludovico Technique please.All of the non-final bosses go down in either 1 or 2 hits. Then there's getting any combination of items that turn Issac from a crying child into an angry winged demon shooting laser beams everywhere.The first time you beat Mom without The Bible is definitely a triumph.
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