Squamous cell carcinoma of the anal canal accounts for 1.5 per cent of all digestive system cancers in the USA, with an estimated 4,660 new cases and 660 deaths in 2006. Epidemiological and molecular-biology studies have now shown that sexually transmitted infection with human papillomavirus (HPV) is the most important aetiological agent. Human immunodeficiency virus (HIV) infection is also associated with anal cancer. HPV infection is transient in most immunocompetent individuals, but HIV-positive patients have evidence of persistent HPV infection within the anal canal. Current data suggest that mutations in p53, DCC and APC tumor suppressor genes contribute to the stepwise progression of anal squamous cell carcinoma in immunocompetent individuals.