For patients who undergo successful surgery for colon cancer, additional chemotherapy is recommended in high-risk stage II and stage III disease. Colorectal cancer prognosis is stage and grade dependent, and many tumors with similar histopathologic features show significantly different clinical outcomes. Therefore, tumor recurrence after curative resection continues to be a significant problem in the management of colon cancer, and approximately 50% of patients will develop recurrent disease. There are a few clinical and potential molecular markers that can predict clinical outcome in locally advanced colon cancer. Accordingly, the development of molecular markers of prognosis is critical in making a tailored adjuvant treatment with molecular stratification possible. Many new biomarkers have been investigated; however, none of them have yet been validated in large prospective clinical trials. To date, the two most promising and most studied mechanisms of genomic instability are chromosomal instability with deletion of chromosome 18q and 17p and microsatellite instability (MSI). Eastern Cooperative Oncology Group 5202 is a prospective clinical trial which is randomizing patients with stage II disease based on their MSI and 18q status to observation versus adjuvant chemotherapy with the intention of prospectively determining their prognostic value as molecular markers. This review will discuss the most promising molecular prognostic markers and provide an update on the most recent developments.