Advances in the understanding of tumor biology have led to the identification of important cellular processes involved in the pathogenesis of colon cancer. Drugs that interfere with these critical pathways are known as targeted agents. The goal of these therapies is to selectively interrupt the signal transduction pathways responsible for tumor growth and survival. Some of these targeted agents have made important, albeit modest, contributions to the treatment of patients with metastatic colorectal cancer. However, the activity levels with the currently available targeted therapies are far lower than experts had hoped, and toxicities are often nontrivial. This article reviews the available therapies, the data that justify their use, and the challenges of optimizing targeted therapies through combinations with cytotoxic chemotherapies and other targeted agents. Finally, some newer drugs and strategies currently being tested in clinical trials are discussed.