There have been substantial advances in the treatment of metastatic colorectal cancer (mCRC) over the past 15 years. Molecular characteristics of mCRC and identification of specific mutations can serve as predictive and prognostic indicators of disease and response to targeted therapies. When incorporated into clinical decision-making, these biomarkers can serve as critical tools in personalizing therapy to ensure the best outcomes. Additional improvements in the survival of patients with mCRC will be made possible with the identification of new predictive molecular biomarkers and their evaluation using rational and innovative clinical trials.