Considerable progress has been made in the treatment of colon cancer from the era when 5-fluorouracil was the only effective agent for this disease. In addition to new chemotherapeutic agents, such as oxaliplatin, irinotecan, and capecitabine, the advent of biologic agents has contributed considerably to the treatment of colon cancer and has improved outcomes. An increased understanding of cancer at the molecular and genetic level has allowed for the development of therapeutics that target the multiple pathways essential to malignant behavior. While currently approved biotherapy in advanced colon cancer is limited to monoclonal antibodies against VEGF and EGFR, many more biologics targeting different pathways of oncogenesis are in development. There is also great interest in combining biotherapy not only with chemotherapy, but also with other biologics. Using rational combination biotherapy could overcome mechanisms of cancer cell resistance and result in synergistic activity. We review the various molecular targets of biologic therapy in colon cancer, discuss the rationale for their use as single agents and in combination, and present clinical evidence demonstrating their efficacy.