He is best known for portraying IMF Agent Luther Stickell in the Mission: Impossible film series (1996–present) and crime boss Marsellus Wallace in Pulp Fiction (1994).

After high school, he studied drama at SUNY Purchase, where fellow acting student Stanley Tucci gave him his nickname "Ving".

Rhames later transferred to the Juilliard School's Drama Division (Group 12: 1979–1983)[3] where he graduated with a Bachelor of Fine Arts degree in 1983.

He started out in film in Wes Craven's The People Under the Stairs (1991) as Leroy, watched over Kevin Kline as Secret Service agent Duane Stevensen in Dave (1993), and played Marsellus Wallace in Pulp Fiction (1994).

Rhames played Dr. Peter Benton's brother-in-law on the TV medical drama ER, a recurring role he filled for three seasons.

He played ace computer hacker Luther Stickell opposite Tom Cruise in Brian De Palma's Mission: Impossible (1996).

"[7] Rhames appeared in Striptease (1996) as the wisecracking bodyguard Shad, Jesus-praising paramedic Marcus in Bringing Out the Dead (1999), and reprised his Luther Stickell role for Mission: Impossible 2 (2000).

He played Johnnie Cochran in American Tragedy (2000), the ex-con boyfriend of Jody's mother in the John Singleton film Baby Boy, portrayed a gay drag queen in the television film Holiday Heart, contributed his voice for the character of Cobra Bubbles in Lilo & Stitch (2002) and the subsequent TV series, and played a stoic cop fighting zombie hordes in Dawn of the Dead (2004) and Day of the Dead (2008) remakes.

In the 2008 film Saving God, he played an ex-con who is released from prison a changed man, looking to take over his father's former church congregation in a deteriorating neighborhood.