Approximately one-third of patients diagnosed with early stage colorectal cancer (CRC) will present with lymph node involvement (stage III) and about one-quarter with transmural bowel wall invasion but negative lymph nodes (stage II). Adjuvant chemotherapy targets micrometastatic disease to improve disease-free and overall survival. While beneficial for stage III patients, the role of adjuvant chemotherapy is unestablished in Stage II. This likely relates to the improved outcome of these patients, and the difficulties in developing studies with sufficient power to document benefit in this patient population. However, recent investigation also suggests that molecular differences may exist between stage II and III cancers and within stage II patients. Validated pathologic prognostic markers are useful at identifying stage II patients at high risk for recurrence for whom the benefit from adjuvant chemotherapy may be greater. Such high risk features include higher T stage (T4 versus T3), suboptimal lymph node retrieval, presence of lymphovascular invasion, bowel obstruction or bowel perforation, and poorly differentiated histology. However, for the majority of patients who do not carry any of these adverse features and are classified as “average risk” stage II patients, the benefit of adjuvant chemotherapy remains unproven. Emerging understanding of the underlying biology of stage II colon cancer has identified molecular markers which may change this paradigm and improve our risk assessment and treatment choices for stage II disease. Assessment of microsatellite stability which serves as a marker for DNA mismatch repair system function has emerged as a useful tool for risk stratification of patients with Stage II CRC. Patients with high frequency of microsatellite instability (MSI-H) have been shown to have increased overall survival and limited benefit from 5FU based chemotherapy. Additional research is necessary to clearly define the most appropriate way to use this marker and others in routine clinical practice.