Colon cancer is a common cause of cancer-related mortality. Complete surgical resection of the primary tumor and/or select metastatic lesions can be curative in many patients. The risk of recurrence after resection can be predicted by pathologic staging. Large prospective randomized trials over the past 2 decades have clearly shown an increased overall survival for patients with resected stage III colon cancer who are treated with adjuvant 5-fluorouracil-based chemotherapy. The benefit of adjuvant chemotherapy for patients with stage II disease remains controversial. There is indirect evidence to support adjuvant chemotherapy after resection of metastatic disease. Locoregional approaches such as radiation, hepatic arterial infusion, or portal vein chemotherapy remain investigational. Adjuvant immunotherapy with monoclonal antibodies is emerging as a therapeutic option that might complement chemotherapy. Future challenges include improving adjuvant chemotherapy with the addition and/or substitution of new agents, resolving which subset of patients with stage II and resected stage IV colon cancer might benefit from therapy, validating the benefit of immunotherapy, and investigating locoregional therapies compared with systemic therapy.