High-risk stage II and stage III colon cancers are associated with significant recurrence rates after surgical resection. Adjuvant chemotherapy has demonstrated a significant disease-free and overall survival benefit for patients, even if not helpful for all. Currently, there are limited clinical and molecular markers that can predict response to chemotherapy and clinical outcome in advanced colon cancer. Herein, we review and discuss recent data about the most promising clinicopathologic and molecular factors described thus far and that are of interest in the management of patients with colon cancer.