Born in Greenwich, London, Difford has written lyrics for over thirty years, most notably in partnership with Glenn Tilbrook. The two were primary members in Squeeze and Difford & Tilbrook. Some of their best-known songs are 'Tempted', 'Pulling Mussels (From the Shell)', 'Black Coffee in Bed', 'Cool for Cats', 'Up the Junction' and 'Annie Get Your Gun'.
After the breakup of Squeeze in 1983 Difford continued writing songs with Glenn Tilbrook for artists such as Helen Shapiro, Billy Bremner and Elvis Costello. He has also written lyrics for music by Jools Holland, Elton John, Wet Wet Wet, Marti Pellow and others. In 1985 Squeeze reunited, having hits in the U.S. with Babylon and On, 'Hourglass' and '853-5937'. Difford left the group in 1999 launching a solo career in 2003 with his album I Didn't Get Where I Am. Difford was also manager of Bryan Ferry and The Strypes. In March 2010, Difford curated Songs in the Key of London, an evening of music dedicated to the capital at the Barbican Centre, London.