Many patients with stage III colon cancer, and selected patients with stage II disease, will obtain significant benefit from adjuvant chemotherapy. Combination regimens that include a fluoropyrimidine plus oxaliplatin are the current standard of care, based on findings from the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) and the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trials. Ongoing randomized trials are evaluating oral fluoropyrimidines combined with oxaliplatin and the addition of targeted therapies to oxaliplatin-based regimens for use in colon cancer adjuvant treatment. Adjuvant treatment approaches for patients with rectal cancer (stage II and III) now include preoperative chemoradiotherapy, based on a phase III comparison of preoperative vs. postoperative chemoradiotherapy conducted in Germany. Ongoing trials are evaluating new cytotoxic and target-oriented agents used in both the neoadjuvant and adjuvant settings in these patients. Improved surgical and radiotherapy techniques may also contribute to superior patient outcomes. Additional research is needed to identify patient subgroups at risk for recurrence, predictive factors for treatment response, and better treatment strategies for patients with colon and rectal cancer.