Concurrent with an expansion in the number of agents available for the treatment of advanced CRC, there has been an increase in our understanding of selection biomarkers to optimize the management of patients with this disease. For CRC patients being considered for anti-EGFR therapy, expanded RAS testing is the standard of care to determine the subset of patients who can benefit from cetuximab or panitumumab in conjunction with chemotherapy. A small fraction of patients have HER2 amplification where emerging data suggest treatment with drugs targeting this alteration. Although advanced CRC patients who harbor the BRAF V600E mutation have a poorer prognosis, they are eligible for combinatorial therapy targeting EGFR/BRAF or BRAF/MEK within the MAP kinase signaling pathway. Once primarily thought to be a negative prognostic marker, BRAF V600E mutation is now considered as a positive predictive factor with an opportunity for clinical intervention. A growing body of evidence also supports MSI testing as clinical benefits with immune checkpoint blockade by cancer immunotherapy have been demonstrated in MSI-high patients whose tumors exhibit high mutational burden. It has been established that UGT1A1*28 polymorphism is associated with irinotecan toxicity, but this test is rarely performed as the management strategy has not been identified. No established predictive biomarker for anti-VEGF therapy has yet to be discovered. It is becoming increasingly apparent that our growing understanding of biomarkers is revolutionizing and improving our strategies in the treatment of advanced CRC. Traditional nonselective cytotoxic chemotherapy is gradually being augmented and even in some cases supplanted by selective targeted agents based on our increasing understanding of tumor signaling and mechanism at the molecular level. The prospect of personalized medicine in directing treatment approaches that are optimally beneficial for patients brings tremendous excitement to the growing field of cancer therapeutics. As discussed in this chapter, the concurrent development of molecular biomarkers with new treatment strategies holds great promise of precision medicine in improving outcomes for patients with advanced CRC.