David Alan Grier starred in his own one-hour standup comedy special in 2003 on Comedy Central entitled The Book Of David-The Cult Figures Manifesto.

He was nominated for a Tony Award for best supporting actor in a musical for his role as Jackie Robinson in the musical The First, directed by Martin Charnin and written by Joel Seigal. He is the winner of the Theatre World Award for The First and The Golden Lion Award for best actor at the Venice Film Festival for the film Streamers, directed by Robert Altman. He hosted his own national late night syndicated TV show in early 2006. He is often referred to as the third host of the radio show Loveline, as a frequent and popular guest.

He has also appeared in films Amazon Women on the Moon, I'm Gonna Git You Sucka, Boomerang, Blankman, Jumanji, BAADASSSSS!, and The Woodsman. He played a major role in the 2005 motion picture remake of Bewitched, and also made a cameo appearance on Blue Collar Comedy Tour: The Movie featuring Jeff Foxworthy and Ron White. He is also a frequent guest on the TV show Crank Yankers.

He is number 94 on Comedy Central's list of the 100 greatest standups of all time.