Cancers of the colon and rectum will affect 1 in 17 North Americans during their lifetime. The progress witnessed in the treatment of these cancers in recent years has been remarkable. Improvements have been realized in surgical technique, radiation therapy, and systemic therapies, particularly with the addition of oxaliplatin and irinotecan to the previously limited armamentarium of fluorouracil alone. Targeted therapies directed at the vascular endothelial growth factor pathway and the epidermal growth factor pathway are now key players in the treatment of colorectal cancer. With current-day therapies, more than 75% of patients with localized disease are recurrence free at 3 years, and up to 50% of patients with advanced unresectable disease are alive at 2 years. This review focuses on the evidence supporting the current role of chemotherapy and radiation therapy in the adjuvant management of colorectal cancers and the strategy of combining chemotherapy and biological therapy in the treatment of metastatic disease.