This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, mutational status, and patient comorbidities and preferences. Location of the primary tumor, the mutation status, and tumor microsatellite stability should also be considered in treatment decisions.