Drugs for specific molecular targets have generated a great deal of excitement for their potential in cancer treatment, particularly with respect to our molecular understanding of cancer in recent years. The clinical utility of antibodies and small molecule kinase inhibitors has been demonstrated. The ErbB family of receptors is at the forefront of targets that are the subject of clinical trials. However, the activities of epidermal growth factor receptor antagonists have not been impressive as single agents. One of the lessons learned with this class of targets is that we currently do not know how to optimally apply them to the treatment of cancer. This review will discuss the issues contributing to this situation and the approaches that are currently being launched to resolve these issues.