Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Advances in therapies over the past decade have led to improved outcomes for many patients. In addition to cytotoxic chemotherapy, advances in our understanding of tumor biology have led to the development of agents targeted against molecular pathways. The addition of these so-called targeted agents has been shown to add further to the activity of chemotherapy combinations and, in some cases, to offer modest survival advantages. However, these agents are not without substantial potential for toxicity. This review will discuss the available therapies and the data to justify the appropriate use and nonuse of targeted therapies in patients with metastatic CRC.