Bam, said the lady.
Nathan Fillion never plays characters other than himself. And, frankly, I'm okay with that.
—The Escapist Unskippable
- Malcolm Reynolds, captain of the Firefly-class vessel Serenity.
- Gunnery Sergeant Edward Buck, one of the main ODSTs in Bungie's Halo 3 ODST. He was with two other Firefly mains, Adam Baldwin and Alan Tudyk. Some joke that he's basically playing Mal with a new name, due to similar personalities, and since they went Ink Suit Actor on him, identical faces and hairstyles, as well as voice.
- Richard Castle, novelist-turned police consultant in the self-titled series Castle.
- Captain Hammer, Dr. Horrible's nemesis.
- Caleb in Season 7 Buffy, evil guy with Catholic priest theme, dragon to the season's Big Bad and the complete opposite of his usual on-screen persona.
- Alex Tully in Drive, another cancelled-after-4-episodes series from Tim Minear.
- Bill Pardy, town sheriff from Slither.
- Steve Trevor, the male romantic lead in the Wonder Woman cartoon movie.
- Dr. Pomatter in the independent comedy Waitress.
The first of those roles earned him most of his recognition, despite the short run of the series. Numerous bit parts include cameos as Buck in Halo Reach, a Sgt. Reynolds in Halo 3, James Frederick Ryan in Saving Private Ryan, and Kate's ex-husband in Lost. Before that, BioWare had him voicing Gao The Lesser in Jade Empire. He also voiced Vigilante in Justice League Unlimited.
He also has a Twitter account and is very good at making Memetic Mutation Catch Phrases such as "Bam, said the lady" and "Feed the birds." Both have had cameos on his hit show Castle (as well as "Double Rainbow", a meme that he didn't start.)
Speaking of Firefly, he said in a recent interview that if he had $300 million, he'd buy the rights to Firefly and make it his own. This being the internet, a brief but passionate movement sprang up to help him do such a thing, but it fell apart due to a lack of official support from Fillion himself and/or Joss Whedon.
Bizarrely, he has been mistaken for Jason Bateman several times by both normal people and celebrities alike to the point where it is a Real Life Running Gag. But of course, Nathan takes no offense to it and continues documenting the instances where it happens because he's just that awesome. It might help that on one of those occasions it got him out of a speeding ticket.
He was also used as Hal Jordan in a fan trailer for the proposed Green Lantern film, which he thought was awesome. Sadly, he was not actually cast in Green Lantern, but he was cast as Green Lantern in the 2011 direct-to-DVD DCAU Green Lantern: Emerald Knights, which is just gorram perfect, if you ask us. He'll reprise the role in Justice League: Doom.
Similarly, he was in talks to play Captain America, but the role went to Chris Evans. Gorram it!  However, he did end up playing a superhero (well, a satirical one anyway) known as The Holy Avenger in Slither director James Gunn's second film Super.
Oh, and he kicked Justin Bieber's ass at Halo: Reach. According to him it "felt good." Also, there are two exceptions to the statement "Only Bungie employees have flaming heads in Halo 3." Those two are a contest winner and Nathan Fillion.
He's also One of Us. Con-goers pass around a story where a few friends sat down for some Firefly pen-and-paper action. Fillion approached the table and purportedly requested to play as... River.