Vos began his stand-up career in 1984, choosing to pursue it full-time as he "failed at everything else", and developed his act in local clubs.
In 1995, Vos became the first white comic to perform a set on Def Comedy Jam on HBO, a show usually featuring African American comedians.
In July 1999, Vos hosted the Woodstock '99 festival, later calling it a highlight of his career.
In 2001, Vos played the bouncer and wrote and performed skits on the British television show The People vs. Jerry Sadowitz. In 2001, Vos released a stand-up comedy album, I'm Killing Here. This was followed by the DVD Vos, consisting of an unedited, 55-minute performance recorded at the Stress Factory in New Brunswick, New Jersey, released in 2004. He went on to produce two half-hour specials on Comedy Central Presents.
In 2003, Vos came third on the first season of Last Comic Standing on NBC. During this time he was given the nickname "The Don" by Cory Kahaney "because of my rough and tough demeanor ... maybe it was more because I was the most experienced comic". At the end of the season, Vos toured with Kahaney and Dave Mordal for eight months. In 2004, Vos was a finalist in its third season.
Vos was a frequent guest on the Opie and Anthony radio show, with jokes centered at his expense, most often highlighting his speech impediment or supposed lack of intellect. In 2002, he brought comedian Patrice O'Neal onto the show who also became a popular regular guest. During the show's time on Sirius XM Satellite Radio, Vos hosted a Saturday night program with Bonnie McFarlane. He hosted the 2006 and 2007 editions of the Opie and Anthony's Traveling Virus Comedy Tour.
From 2002 to 2004, Vos was a frequent guest on Tough Crowd with Colin Quinn on Comedy Central. He picked the show as one of his favourites to do as he lived close to its filming location and by the fact that he could do it with his best friends.
Between 2006 and 2008, Vos prepared three pilot episodes for a comedy series alongside McFarlane, but neither were picked up by a network.
Vos has appeared on Premium Blend. He was featured in a segment of the television show, What Would You Do? In November 2011, Vos began a podcast with McFarlane titled My Wife Hates Me.
In December 2016, Vos released his fifth comedy album V, of which its material took between one year and a half and two years to develop. It charted at number one on the iTunes and Billboard release charts.