As the cost of cancer care in the United States continues to climb at an alarming rate, it is critically important for the oncology community to begin embracing interventions that provide value to patients and society. This is particularly important in the field of colorectal cancer, where many new high-priced drugs have emerged over the past several years. While adjuvant chemotherapy (FOLFOX and capecitabine) has been shown to fall within accepted thresholds for cost-effectiveness, many interventions in the metastatic setting have not. Bevacizumab in the first- and second-line settings as well as EGFR inhibitors across all lines of therapy have been associated with unfavorable cost-effectiveness ratios in several studies conducted in the United States and other countries. A key strategy in improving the cost-effectiveness of CRC treatment in the advanced setting will therefore be to identify predictive biomarkers (e.g., RAS mutation) for therapeutic response to existing drugs as well as drugs in development so that high-priced therapies can be administered to patients most likely to benefit and avoided in those who would not.