Over the past 20 years, substantial advances have been made in the treatment of patients with metastatic colorectal cancer (mCRC). In particular, there is now a wide range of options for the front-line treatment of mCRC. Sophisticated molecular technologies have been developed to identify novel prognostic and predictive biomarkers for CRC. DNA sequencing technology has made remarkable advances in recent years, primarily as a result of the development of next-generation sequencing and whole exome sequencing, which are powerful new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of personalized medicine. In addition to tumor tissue, recent efforts have focused on analyzing circulating tumor DNA in peripheral blood. Herein, we review the evolution of standard chemotherapy and targeted therapy strategies for the treatment of mCRC in the front-line setting, the molecular technologies that are presently being used to facilitate our ability to practice individualized medicine, and the practical aspects of applying molecular biomarkers to everyday clinical practice.