Colorectal cancer (CRC) is the second most common cause of cancer mortality in the United States. Despite advances in therapy, metastatic CRC remains lethal, and further improvements in therapy are needed. Growing understanding of cancer biology, particularly in growth factor signaling, angiogenesis, and cancer immunology, has translated into many novel therapies under investigation. Patients are increasingly selected for clinical trials rationally on the basis of integral biomarkers. This review discusses several promising agents in development for metastatic CRC.