A number of advances have been made in the use of adjuvant chemotherapy for resectable rectal cancer. Whereas pelvic radiation therapy has been shown to increase local control in patients with clinically resectable disease, systemic chemotherapy is needed in addition to further improve local control and overall survival. In this review, the experience treating patients with clinically resectable rectal cancer in the postoperative adjuvant setting will be examined. Data from ongoing and recently completed randomized trials as well as the design of innovative phase I/II programs will be discussed.