John L. Marshall, MD; Marwan G. Fakih, MD; Arvind N. Dasari, MD, MS, MD, and Katrina S. Pedersen, MD discuss how precision medicine has transformed metastatic colorectal cancer treatment through comprehensive molecular testing, targeted therapies like BRAF/EGFR inhibition and immunotherapy combinations for MSI-high tumors, and personalized approaches to treatment sequencing and dosing modifications that balance efficacy with quality of life considerations.