After playing with Blood, Sweat & Tears, he worked with drummer Billy Cobham, then with trumpeter Miles Davis from 1981 to 1983 and again in 1985.

[3] When he was twenty-two, he became a member of Blood, Sweat & Tears and spent three years with the band,[4] appearing on the albums More Than Ever and Brand New Day.

The quintet released one album, the Nils Lofgren-produced Daddy's Girl, in 1976 before Stern left the group.

[6] Stern's solo debut, Upside Downside, with Jaco Pastorius, David Sanborn, and Bob Berg, was released on Atlantic Records in 1986.

His next album, Jigsaw, was produced by guitarist Steve Khan and included the song "Chief", Stern's tribute to Miles Davis.

His acclaimed 1993 album, Standards (and Other Songs), led to his being named Best Jazz Guitarist of the Year by the readers and critics of Guitar Player.

In 1997 he released Give and Take, with bassist John Patitucci, drummer Jack DeJohnette, percussionist Don Alias and special guests Michael Brecker and David Sanborn.

After fifteen years with Atlantic, Stern signed with ESC Records for the 2004 release of These Times, an eclectic album that included guest appearances by bassist Richard Bona, saxophonist Kenny Garrett and banjoist Béla Fleck.

In February 2009, in the first of a series of articles celebrating Down Beat's 75th anniversary, Stern was named one of the 75 Great Guitarists of all time.

In August 2009, Stern released Big Neighborhood, which was nominated for a Grammy Award for Best Contemporary Jazz Album.

An early and important guitar for Stern was a hybrid 1950s/1960s Fender Telecaster, previously owned by Roy Buchanan and Danny Gatton, which was stolen from him in an armed robbery in Boston.