Metastatic colorectal cancer (mCRC) is incurable in patients with unresectable disease. For most patients, the primary treatment is palliative systemic chemotherapy. Genomic profiling is used to detect specific genetic mutations that may offer selected patients a modest survival benefit with targeted therapy. Patients with mCRC with KRAS/NRAS/BRAF wild-type left-sided tumors may benefit from epidermal growth factor receptor (EGFR) inhibition with either cetuximab or panitumumab, in conjunction with chemotherapy. EGFR inhibitors can extend survival by 6 months compared with chemotherapy alone. The vascular endothelial growth factor (VEGF) inhibitor bevacizumab can serve as an alternative to EGFR inhibitors in right-sided tumors or second-line therapy. Many patients will have RAS mutations, and targeted therapies will not provide any benefit. The PRIME trial demonstrated that the addition of panitumumab to FOLFOX was associated with reduced overall survival. Patients with BRAF mutations do not benefit from targeted therapy unless a BRAF inhibitor supplements treatment. Triple combination therapy with cetuximab, the BRAF inhibitor encorafenib, and the MEK kinase inhibitor binimetinib has extended overall survival by about 3 months compared with chemotherapy alone. Finally, for the minority patients with microsatellite instability (MSI) high/mismatch repair (MMR) deficient tumors, either due to Lynch syndrome or sporadic mutations, immunotherapy is recommended as first-line treatment. The KEYNOTE-177 trial demonstrated that therapy with single-agent pembrolizumab improved progression-free survival by 8 months compared with FOLFOX or FOLFIRI and with or without EGFR inhibition. At this time, targeted therapy should only be used in patients with unresectable metastatic disease.