During the past two decades, anal cancer has served as a paradigm for the successful application of chemoradiation to solid tumours; so far, it remains one of the few carcinomas of the gastrointestinal tract which are curable without the need for definitive surgery. Since the original contribution by Nigro in 1974, surprisingly few changes have been made to the standard of care in chemotherapy, which still consists of a combination of 5-fluorouracil and mitomycin C. However, many issues have yet to be clarified, such as the potential role of cisplatin as a substitute to mitomycin, as well as treatment-induced toxicity in HIV-positive patients. In this paper, the management of patients with anal cancer is presented, and new chemotherapeutic options are critically reviewed. Finally, the authors' opinion regarding currently unresolved issues in the treatment of these rare neoplasms is expressed.