Combined modality therapy (CMT) with radiation therapy and chemotherapy plays an important role in the management of rectal cancer. Postoperatively, pelvic irradiation and 5-fluorouracil-based chemotherapy have been used to improve local control and survival for high-risk patients after local excision, as well as for patients undergoing abdominoperineal or low anterior resection. For patients treated preoperatively, CMT can also be used to facilitate sphincter-sparing surgery for distal rectal tumors. Preoperative CMT in conjunction with surgery and intraoperative radiation therapy has been useful for patients with locally advanced and recurrent rectal cancer as well. While chemotherapy has benefit for patients with stage III colon cancer above the peritoneal reflection, the role of CMT is less well defined. Retrospective reviews suggest improved local control and survival in subgroups of patients treated with postoperative radiation therapy and chemotherapy. Active areas of investigation in CMT for colorectal cancer include the integration of biologic predictors, radiation modulators, and novel systemic agents.