In 1967 Griffin began collaborating with singer/keyboardist Robb Royer, a member of the harmony pop quartet Pleasure Fair. The group's 1968 self-titled LP was produced by in-demand L.A. session musician David Gates, and when the Pleasure Fair dissolved soon after, Gates recruited Griffin and Royer to form Bread. Bolstered by Griffin/Royer songs like "Friends and Lovers," "Could I," and "Any Way You Want Me," Bread's eponymous 1969 debut was first and foremost a showcase for Gates, whose "It Don't Matter to Me" proved a massive radio hit. Favoring lush harmonies and gentle arrangements that contrasted sharply with the harder-edged sounds then dominating FM radio, the album was instrumental in midwifing the soft-focus melodicism that would enjoy commercial supremacy throughout the decade to follow, and made Bread superstars. In 1970 Griffin and Royer were asked to set lyrics to Fred Karlin's music for the film Lovers and Other Strangers; "For All We Know," performed on the soundtrack by Larry Meredith, went on to win the Oscar for Best Original Song, later becoming a massive radio hit when covered by the Carpenters.

While Bread notched a total of ten Top 20 hits, among them "Make It with You," "If," and "Baby, I'm a-Want You," fewer of Griffin's songs made it on each of the group's successive albums, and in frustration he broke ranks following 1972's Guitar Man; two years later he resurfaced with a solo LP, Breakin' Up Is Easy. After rejoining Bread for 1976's ill-conceived reunion effort Lost Without Your Love, Griffin issued his third solo record, 1977's James Griffin, before teaming with ex-Hollies vocalist Terry Sylvester for 1981's one-off collaboration Griffin and Sylvester. Five years later he resurfaced alongside Billy Swan and Randy Meisner in the harmony supergroup Black Tie, and during the 1990s worked with Cymarron's Richard Mainegra and Rick Yancey in the Remingtons. Griffin was performing with Sylvester and John Ford Coley when cancer claimed his life on January 11, 2005.