Since the late 1980s and early 1990s, 5-fluorouracil-based chemotherapy has been the standard adjuvant treatment for Stage III colon cancer. After the initial introduction of 5-fluorouracil in standard treatment protocols, several changes have been made based on results of randomized studies on various treatment regimens, including new cytotoxic agents. In Stage II patients, the role of adjuvant chemotherapy is debatable. However, there might be a role for adjuvant treatment in certain high-risk patients. Following a search of the Medline database, the results of randomized studies on 5-fluorouracil-based adjuvant therapy are reviewed, and future therapeutic options are discussed.