Due to its frequency and persistently high mortality, colorectal cancer represents a major public health problem. The use of adjuvant chemotherapy has improved prognosis in stage III disease, but much work remains to be done in optimizing adjuvant treatment, including refinement of ability to predict disease course and response to chemotherapy. The FOLFOX4 regimen is now considered standard treatment for stage III disease. Combinations of irinotecan and 5-fluorouracil (5-FU) have not proven to be more effective than 5-FU/folinic acid (FA). Oral fluoropyrimidines (eg, capecitabine, UFT + FA) now offer an alternative to intravenous 5-FU. Adjuvant chemotherapy for stage II colorectal cancer is more controversial. Use of adjuvant chemotherapy does not appear to be justified in patients with no particular risk factors (T3N0 with no poor prognosis factor). In contrast, the risk:benefit ratio in patients with one or more poor prognostic factors (T4 tumor, occlusion or perforation, poorly differentiated tumor, vascular invasion, or < 10 lymph nodes examined) appears to favor adjuvant treatment with FOLFOX4. Ongoing adjuvant trials are evaluating bevacizumab and cetuximab combined with 5-FU and oxaliplatin, and are examining the utility of such potential predictive markers as tumor microsatellite instability and loss of heterozygosity. Duration of therapy and prevention of oxaliplatin neurotoxicity are other critical areas for future research.