The decision about who may derive benefit from adjuvant chemotherapy in colon cancer is often a difficult one for clinicians. While multiple trials have demonstrated that adjuvant chemotherapy reduces the risk of recurrence and improves overall survival in patients with stage III disease, the data supporting the use of adjuvant chemotherapy in patients with stage II disease are not as compelling. Because adjuvant therapy can have significant toxicity, tools to help clinicians determine who may derive a benefit from therapy are of the utmost importance. Recent advances in high throughput technologies have led to the identification of molecular biomarkers-including microsatellite instability (MSI), loss of heterozygosity (LOH), p53, Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), thymidylate synthase (TS), and excision repair cross-complementation group 1 (ERCC1)--as well as various multigene assays that are being studied for their ability to offer both prognostic and predictive information to clinicians. Here we review the current knowledge about molecular biomarkers that may aid the clinician in offering personalized cancer therapy based on the genetic landscape of an individual patient's tumor.