Combined-modality therapy, including irradiation and concurrently administered chemotherapy, has become the mainstay of therapy for anal and rectal cancers. Several important lessons have been learned from clinical trials over the last several decades. Simultaneous delivery of large (bolus) doses of 5-fluorouracil with irradiation is associated with improved survival compared to irradiation alone, but at a price of increased normal tissue toxicity. These side effects can be ameliorated by using protracted venous infusion for chemotherapy, which is analogous to the observations in radiation oncology that fractionation spares late tissue toxicity. The protracted venous infusion approach is efficacious, has a wide therapeutic index, and permits concurrent systemic treatment of micrometastatic disease and radiation sensitization. Protracted venous infusion chemoradiation is also used in the preoperative management of rectal cancer and in the nonoperative management of anal cancers. Newer radiosensitizing agents, three-dimensional radiotherapy planning, and conformal radiotherapy treatment offer additional hope for the future that even more patients with rectal and anal cancers may benefit from combined-modality therapy with acceptable toxicity.