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Fillion first gained recognition for his work on One Life to Live in the contract role of Joey Buchanan, for which he was nominated for Daytime Emmy Award for Outstanding Younger Actor in a Drama Series, and for his supporting role as Johnny Donnelly in the sitcom Two Guys and a Girl.

After working in several theatre, television, and film productions, including Theatresports with Rapid Fire Theatre and the improvised soap opera Die-Nasty, Fillion moved to New York City in 1994 where he acted in the soap opera One Life to Live as Joey Buchanan, for which he was nominated in 1996 for a Daytime Emmy Award for Outstanding Younger Actor in a Drama Series.

In 2014 he appeared in the video game Destiny as the character Cayde-6 as a somewhat minor character.

He is the subject of two works of contemporary public art by Firrell: Complete Hero (digital projections of text and video portraiture to the West and North elevations of the Guards Chapel, Wellington Barracks, London, 2009) Fillion was the 'face' of Complete Hero.

The artist explained the choice of Fillion as follows: "I wanted to make a piece of work that looked at all kinds of heroism, not just the usual derring-do of white square-jawed men.

Horrible's Sing-Along Blog, television soap operas and sitcoms, and theater.

Fillion has also voiced several video games, including the Bungie titles Halo 3, Halo 3: ODST, Halo: Reach, Destiny, and Destiny 2, along with the 343 Industries video game Halo 5: Guardians.