The management of colorectal cancer (CRC) has changed considerably in the past 15 years with the introduction of multiple novel active therapeutic agents. Chemotherapy regimens combining a fluoropyrimidine with either oxaliplatin or irinotecan are standard first-line and second-line therapy for advanced and metastatic disease. The first-line use of these combinations produces tumor response rates of approximately 50% and a median overall survival of approximately 20 months. Addition of bevacizumab to first-line treatment and addition of cetuximab to salvage therapy for patients who fail to respond to irinotecan have contributed to further increases in tumor response rates and enhanced progression-free survival. Such approaches have produced only marginal overall survival benefits, however, and entail considerable cost. Adjuvant chemotherapy, delivered after surgical resection of the primary tumor, increases cure rates by approximately 10% for stage III disease and approximately 3-4% for stage II disease. Encouraging reductions in local relapse rates have been observed in patients with early rectal cancer who have undergone chemoradiotherapy, and increasingly complex regimens are currently being explored in phase II clinical trials in an attempt to increase both the operability and long-term local control of CRC. The greater the therapeutic choice, the greater the cost (both financial and in terms of toxicity), thus the keener the clinical community becomes to develop biomarkers to select patient populations who will be most likely to benefit from a specific agent.