A frequent quandary for oncologists is the selection of chemotherapy and biologic therapy for patients with metastatic colorectal cancer in second-line and higher treatment settings. While not approved by the US Food and Drug Administration (FDA) in the first-line setting, the vascular endothelial growth factor (VEGF)-targeting agents ziv-aflibercept and ramucirumab are appropriate treatment options in the second-line setting, as is continuation of first-line bevacizumab. Tumor RAS mutational status is helpful to determine which patients may benefit from epidermal growth factor receptor (EGFR)-directed therapies, and other novel biomarkers (BRAF, HER2, and mismatch repair deficiency) allow us to select patients who may benefit from biologic therapies that are FDA-approved for other malignancies. Maintenance therapy for patients with stable disease following first-line therapy is a unique clinical situation that warrants special attention. Immunotherapy has thus far been ineffective for patients with mismatch repair-proficient tumors, but novel combination strategies are being studied to break through this treatment barrier. Finally, several new biologic therapies with novel targets are under development and will likely contribute to the growing arsenal of treatment options for patients with metastatic colorectal cancer.