Adjuvant chemotherapy for colon cancer and combined chemotherapy and radiation therapy (RT) for rectal cancer increases the proportion of patients cured of their disease. Adjuvant chemotherapy is indicated for stage III colon cancer, and although controversial for stage II disease, there is evidence to suggest that these patients may benefit as well. Adjuvant chemotherapy and RT is recommended for patients with stage II/III rectal cancer. Studies incorporating oral fluoropyrimidines as well as combination chemotherapy have been completed, with results demonstrating the value of these approaches. A new generation of studies will evaluate the biologic agents bevacizumab and cetuximab in the adjuvant therapy of colorectal cancer. For rectal cancer, optimal outcomes are dependent not only on the systemic therapy, but also on the expertise of the surgeon and the timing of RT, with improved local control and toxicity seen with preoperative therapy.