First time, no any time you use a Fat Man and watch the glorious explosion afterwards. Especially if your first time is the Super Mutant Behemoth attack in the Galaxy News Radio station, with the Brotherhood's best watching you in awe as you, a random wastelander, blows the giant to kingdom come.
And the MIRV is a Fat Man in freaking shotgun mode. It goes without saying that it is exponentially more awesome than a Fat Man.
The Experimental MIRV classes as a Gun of Awesome. No matter what you decide to use it on, it always leaves your mouth watering.
As the name implies, testing the weapon in different situations in the game and launching or even glitching your own character by firing into the ground turns The Experimental MIRV into it's very own Sidetracked by the Gold Saucer.
Nuking Megaton and watching as the Evil Points just roll in.
Mothership Zeta has something even better: at one point you are in the ships laser control room and can FIRE THE LASER AT EARTH!! Needless to say, the destruction caused by this blows Megaton away. Well, figuratively speaking. Not literally. Best anybody can tell the laser was aimed somewhere near Toronto.
Everything and anything with LIBERTY PRIME in it, especially the first time you see it. They tell you that you and your allies will be leading the assault and the robot will be sent as back-up. Nuh-huh, the robot is leading the assault and your job is to find a good spot from which to view the epic Curb-Stomp Battle. Nothing stands in his way, or at least it doesn't stand for long before he blows it up.
Probability of mission hindrance : ZERO PERCENT! Battle analysis: Red Chinese Victory IMPOSSIBLE! Democracy is NON negotiable! Embrace democracy, OR YOU WILL BE ERADICATED!
Consider how long it took you to cover that kind of distance in the Capital proper earlier in the game, and behold how Liberty Prime strides unchecked through the heart of the city, straight up to the purifier complex, plowing through dozens of Power Armor equiped Enclave troopers like he was walking across the street for a loaf of bread.
Paradise Falls is widely regarded as one of the best gunfights in the game.
Any video where "the annoying man" gets executed is both awesome and hilarous at the same time. And even though you said agreed to escort him, you don't lose any karma at all if you kill him!
After completing Operation: Anchorage, you get access to the Chinese Stealth Suit, which essentially grants you infinite Stealth Boy use while in sneak (crouch-walk) mode. Stealth Boys cloak you and makes you damn near undetectable, and coupled with a high Sneak skill you can literally hit people with your fists and only get a "Caution" on your sneak indicator. While it is pretty fun being able to get guaranteed Sneak-crits on enemies with a Sniper Rifle with their allies not even noticing (despite talking to the victim as the shot hits), nothing is quite as fun as equipping the Deathclaw Gauntlet, sneak up on anyone, anywhere and send them flying dismembered away with a single hit. And no one ever notices as long as you one-hit kill them! Hilarity ensues as you enter Megaton Predator-style, kill people without a trace of ever being there, then eat the corpse with the Cannibalism perk. You can then proceed to stand up and drag the body through town, and all you will ever get as a response is a dry "Are you having fun with that thing?" or an annoyed "Stop doing that."
Fawkes is awesome in general. Not only was he planning on breaking you out of the motherfucking Enclave base with a Gatling Laser he apparently got hold of in a few hours for that express purpose, but he's also capable of taking down anything on his own.
Fawkes versus a dozen mercs and some raiders taking potshots with hunting rifles? They're all fucked.
At the end of the Broken Steel quest "Who Dares Wins" you get to launch an orbital strike on the Enclave's airforce base! This is of course after you fight your way through the entire base full of Enclave troops. The most satisfying moment is when you realise just how royally screwed they are now after causing you and the wasteland so much trouble.
If you're evil, though, you can turn the weapon on the Brotherhood of Steel, wiping them out as well. Laughing maniacally as you wipe out the scant remnants of their organization is optional.
Managing to find and put together all the junk you need to create all of the makeshift weapons like the bottle cap mine or deathclaw gauntlet, then testing them all out on a group of raiders or other annoying foe. Nothing beats killing Demonic Spiders with the random trash you find lying around the wasteland.
Particularly so for the Rock-It Launcher, is there anything more rewarding than slaughtering your foes with the cuddly wuddly death of a thousand teddys?
Using pre-war PAPER money?
The finale of the Mothership Zeta DLC, where you engage in a space battle with another alien ship.
Especially when the little girl you've been traveling with treats it as if it were the climatic finale of an epic sci-fi TV series/movie/videogame.
Going to Old Olney armed with nothing but a Dart Gun, a Chinese Pistol, and a huge stockpile of 10mm ammo, and proceeding to Cherry Tap the Deathclaws into oblivion.
What about going in, unarmed, with 100 unarmed skills, Grim Reaper's Sprint, 10 strength, and paralyzing palm? And slaughtering every single deathclaw one by one with your bare hands? Just use V.A.T.S, and nine out of ten times, the paralyzing palm will knock the deathclaw to the ground and, well... paralyze them. Then, you're free to beat the deathclaw to death. With your bare hands. Repeat 20+ times for all the deathclaws there. Memetic Badass rampage if there ever was one (just make sure to bring a few stimpacks so you can survive until your action points recharge in case paralyzing palm doesn't hit).
Argyle killing Penelope Chase, the former leader of the slavers:
Penelope Chase: Don't try anything funny, zombie.
Argyle: Why, miss Chase, there isn't anything funny about... THE EAGLE CLAW!
There's something poetic about taking out Enclave soldiers, equipped with the highest level of technology, with jury-rigged Wasteland weapons like the Rock-It Launcher, the shiskebab, or the Nuka-Grenade. Imagine a soldier having to drag himself back to Autumn, having to explain that his squad just got annihilated by a can of soda, and a high velocity teddy bear.
Killing Mr. Burke before he can shoot Sheriff Simms in the back, while not as completely awe-inspiring as some of the above events, is still awesome, because it shows that taking a good path did not mean taking a boring one.
Not sure which is better: Watching a randomly spawned Albino Radscorpion kill a Super Mutant Behemoth, or (thanks to Paralyzing Palm) beating a Behemoth to death with one's bare hands.
Dogmeat with the Broken Steel DLC is just amazing. Due to a glitch involved with leveling up, he has his health rise exponentially every time you gain a level. Assuming you found him early in the game, this means you can send him up against a veritable Supermutant Army on his own, and watch him come out with nary a scratch. At level five. Add on the Puppies! perk, which allows Dogmeat to respawn as a younger version of himself outside Vault 101, and you have the downright best companion in the game.
This is true of all companions in Broken Steel. Minus the "respawning outside Vault 101" bit, but it's not like they're ever going to die.
If you got the Point Lookout DLC and got the quest to destroy the book in the Dunwich Building and you do so. After some Fridge Brilliance and a little thinking it hits you. You just destroyed the freaking Necronomicon. You did what thousands of Call of Cthulhu investigators failed to do.
How can watching your dad punch out deathclaws with his bare hands not be a Moment Of Awesome? Daddy loves his little boy/girl very much, yes he does.
How about if he decided to skip over all the assault rifles dropped by raiders and instead pick up a sledgehammer?! Suffice to say, the next encounter with Super-Mutants got infinitely more awesome as a result.
The first time, no any time, you use the train in the Presidential Metro to get to Adams AFB after clearing out those damn feral ghouls ( listed as the security breach by M.A.R.G.O.T.) in Broken Steel. Suffice to say, after trekking through every subway system in the Capital Wasteland only to find out that the War did them in and rendered every train line unusable, while in The Pitt, you use a handcart to travel there but no actual cutscene is portrayed, it's a refreshingly breathtaking moment from all the ruins you've seen everywhere in the wastes to have a fully functional train to ride inafter over 200 years from an apocalyptic war.
Completing the quest "Stealing Independence." Having fought your way through the hordes of Super Mutants in order to save the Declaration of Independence, you may come to the conclusion that this really is much more than just a piece of paper. Thousands, nay millions, have fought for the ideals it stands for. You are now one of those proud few.
Burke's an asshole, sure, but when Roy Phillips tries threatening him after his successful clearing out of Tenpenny Towers, he threatens Burke with the same fate as everybody else... but Burke merely threatens him back, and Roy starts back-pedalling and offering to make him his Number Two. If you've left Burke alive, this moment is quite impressive.
Towards the end of Mothership Zeta, by going off the beaten path, you'll find Toshiro, the Samurai you freed from cryostasis, surrounded by dead aliens. Then during the finale, Sally let's him into the control room where he proceeds to annihilate every wave of Aliens who storm in soon after.
Even better, if you help him along with the cowboy and the pre-War soldier. Think about it: The samurai, the cowboy, the pre-War soldier and you represent different periods of human history, and you are all destroying the alien invaders as payback for the centuries of abductions. You are all sending the aliens a message, and the message is simply this: "Don't fuck with the human race!!'' Showcased beautifully with the name of the last mission: The Galaxy Ain't Big Enough...
Hell, playing the game for the first time and hearing the menu music is a CMOA itself. It leaves quite an impression.