The treatment of colorectal cancer has undergone enormous changes in the past decade. From a disease with a single treatment option (ie, fluorouracil, a modestly effective drug), the treatment options have evolved to include at least five new classes of antineoplastic agents. Among the considerable number of recently approved drugs, two are monoclonal antibodies and are the testing ground for our rapidly emerging knowledge about cancer cell biology. Cetuximab (Erbitux) targets the epidermal growth factor receptor, an important molecule involved with cell cycling, survival, invasion, and metastasis. Bevacizumab (Avastin) neutralizes the vascular endothelial growth factor, blocking its ability to activate its receptor on the endothelial cells. The development of both antibodies resulted from decades of research in molecular and cell biology, as well as preclinical and clinical studies, and signals a new paradigm where the tumor cells' own unique features are exploited in a rational way.