Chemotherapy agents available for the treatment of stage II and stage III colon cancer have changed substantially since the 1992 National Institutes of Health consensus report recommended that all stage III patients routinely receive adjuvant treatment with 5-fluorouracil/levamisole. Subsequent trials demonstrated superiority of 5-fluorouracil/leucovorin over 5-fluorouracil/levamisole in the adjuvant setting, and the recent addition of oxaliplatin to this regimen has further improved disease-free survival. While stage III colon cancer patients are routinely treated, the use of adjuvant chemotherapy in patients with stage II disease is still a subject of debate. Many trials that are assessing the potential role of biologics in the adjuvant setting will soon be completed. However, identifying molecular prognostic markers that accurately select patients with stage II or III cancers who are at risk of recurrence would be essential to select and individualize therapy.