Colorectal cancer (CRC) is the third most commonly diagnosed cancer in men and women in the United States, with a predicted 154,000 new cases this year. For > 40 years, 5-fluorouracil (5-FU) has remained the central agent in therapeutic regimens used in the treatment of CRC, with single-agent response rates (RRs) of 20%-25% in advanced-stage disease. The past decade has witnessed the introduction of newer agents, such as the DNA-damaging agents oxaliplatin and irinotecan, which when used in combination with 5-FU, have dramatically increased RRs to 40%-50% in advanced disease and improved overall survival. The development of monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor have now demonstrated additional clinical benefit for patients with metastatic disease, and the clinical development of these agents continues to progress. However, many patients will die, and a significant proportion will experience severe chemotherapy-induced toxicities, while deriving little or no benefit. Global efforts are currently under way to identify reliable and validated cassettes of markers with the ability to predict response and toxicity from a chemotherapeutic regimen. In addition, the ability to accurately predict patients with early-stage disease at high risk of recurrence will enable the appropriate administration of adjuvant therapy. The emerging cancer stem cell hypothesis continues to gain momentum with ongoing research, suggesting this might become one of the prime targets for future therapy. Together, these approaches are spearheading a paradigm shift toward individualized treatment strategies in CRC treatment.