The treatment of advanced colorectal cancer has definitely advanced in the last 10 years as newer and more active cytotoxic chemotherapy agents have become available. Better understanding of different fundamental molecular changes in carcinogenesis has resulted in the emergence of important therapeutic targets in colon cancer treatment. The era of nihilism has been replaced by a time of optimism with the development of targeted therapy, with the promise of agents with improved activity and a better toxicity profile in the management of colon cancer. This review focuses on novel agents, particularly targeted therapy in both earlier and more advanced phases of clinical investigations.