The treatment of stage II colon cancer is a controversial issue that has persisted for the past decade. Clinicians must understand that accurate assessment of risk factors is the key to identifying patients who will benefit from treatment. Pathologic staging for colon cancer is based on the American Joint Committee on Cancer 6th edition staging system. In addition, distinct pathologic factors characterize a patient at high risk for stage II disease. More recent retrospective data suggest that molecular markers and gene expression microarrays may be valuable as prognostic and predictive tests. Unfortunately, previous research studies were not powered to properly assess efficacy in stage II disease. However, 2 recent clinical trials, National Surgical Adjuvant Breast and Bowel Project C-07 and MOSAIC, have provided more insight into defining the optimal treatment approach. With the development of the newer therapeutic agents, oxaliplatin and bevacizumab, ongoing trials such as Intergroup E5202 should help determine risk versus benefit of chemotherapy in the adjuvant treatment of stage II colon cancer.