Optimal treatment of colorectal cancer requires a multimodality approach. For maximum therapeutic benefit, the biologic basis of all therapeutic components in all treatment disciplines should be understood and exploited. Adjuvant chemotherapy has significantly improved disease-free and overall survival rates, and adjuvant radiation has provided tremendous benefit by improving local-control rates and avoiding the morbidity associated with recurrent disease. Tumor regression in response to preoperative chemoradiation therapy has allowed increased use of sphincter-preserving surgical procedures with excellent functional outcomes, even for locally advanced tumors of the distal rectum. Sphincter preservation may be possible in even more cases as the ability to clear microscopic disease improves, especially disease in the mesorectum. Newer chemotherapeutic agents hold promise for further improvements because of their increased systemic activity and their synergistic effects with radiation.