Anal cancer accounts for 1.5% of digestive system malignancies in the United States. In the past 30 years, substantial progress has been made in understanding the pathophysiology and treatment of the disease. Anal cancer was once believed to be caused by chronic local inflammation of the perianal area, and treatment was abdominoperineal resection. From epidemiologic and clinical studies, we now know that the development of anal cancer is associated with human papillomavirus infection and that the disease has a pathophysiology similar to that of cervical cancer. Less invasive treatments have also been developed, and the majority of patients with anal cancer can now be cured with preservation of the anal sphincter using concurrent external-beam radiation therapy and fluorouracil (5-FU)/mitomycin (Mutamycin) chemotherapy. Current areas under investigation include the incorporation of platinum agents into the chemotherapy regimen and the use of cytologic screening studies for high-risk populations.