Born in Greenwich, London, Difford has written lyrics for over 40 years, most notably in partnership with Glenn Tilbrook. The two were primary members in Squeeze and Difford & Tilbrook. According to Difford, he stole 50p from his mother's purse to put a card in a local sweetshop window advertising for a guitarist to join his band, although he did not have one at the time. Tilbrook was the only person who responded to the advert and they met for the first time shortly afterwards. 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".
Chris Difford performing at London's Royal Albert Hall, October 2009, in aid of the PRS (Performing Right Society) for Music Members' Benevolent Fund.
After the break-up of Squeeze in 1983 Difford continued writing songs for artists such as Jools Holland, 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. He was involved with Tilbrook and John Turner in the creation of a musical, Labelled with Love, which was created using the songs of Squeeze. The 1983 musical performed in Deptford was short-lived. In 1984 the pair released the album Difford and Tilbrook and had a minor hit in the UK with Love's Crashing Waves which reached 57 in the UK charts. In 1985 Squeeze reunited, having hits in the US 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. Squeeze reunited again in 2007, and Difford maintains a concurrent solo career alongside his work with the band.
In 2017, Chris published his autobiography Some Fantastic Place: My Life In and Out of Squeeze.