Squamous cell carcinoma of the anal canal serves as a paradigm for the successful application of multimodality treatment of solid tumors. Since 1974, multimodality treatment with combined radiation and chemotherapy has become the standard. The compelling advantage of sphincter preservation and the substantial survival benefit compared with surgery alone prompted investigators to adopt chemoradiation treatment. Several questions regarding the optimal radiation dose and chemotherapy in initial as well as salvage therapy remain, and only recently have results of several prospective randomized studies become available to address some of these unresolved issues. We reviewed the clinical aspects and historical treatment results of anal canal and perianal epidermoid cancers in light of the results of these modern trials. Current management strategies are redefined, and future directions of clinical studies are outlined.