The use of combined-modality therapy programs, including systemic chemotherapy plus radiotherapy, are being studied intensively, since pilot trials have consistently shown improvement in 1- or 2-year survival statistics compared with historic controls. The mechanisms of interaction of the most popular chemotherapeutic drugs (5-FU, mitomycin C, and cisplatin) when used with irradiation are not fully understood. Further clinical work will be necessary to optimize the best combination of agents, their dose levels, and method and schedules of administration. Pathologic complete responses ranging from 37 to 45% have been reported in some series using preoperative chemoradiation and may translate into better survival rates for some patient subgroups. Several randomized multiinstitutional trials are underway to assess the utility of chemoradiation in comparison to radiotherapy alone in order to confirm these initial encouraging results. From these data, it would be prudent to consider the use of 5-FU continuous infusion treatment with or without other chemotherapeutic agents in conjunction with conventionally fractionated irradiation. Radiotherapy should be given in a continuous fractionated course rather than given as a split course. With these guidelines, the acute complications and late complications seem to be acceptable and not increased over those expected with radiotherapy alone.