The biology of the human epidermal growth factor (EGF) receptor-2 (HER2) has been reviewed numerous times and provides an excellent example for developing a targeted cancer therapeutic. Herceptin, the FDA-approved therapeutic monoclonal antibody against HER2, has been used to treat over 150,000 women with breast cancer. However, the developmental history of Herceptin, the key events within the program that created pivotal decision points, and the reasons why decisions were made to pursue the monoclonal antibody approach have never been adequately described. The history of Herceptin is reviewed in a way which allows the experience to be shared for the purposes of understanding the drug discovery and development process. It is the objective of this review to describe the pivotal events and explain why critical decisions were made that resulted in the first therapeutic to successfully target tyrosine kinases in cancer. New approaches and future prospects for therapeutics targeting the HER family are also discussed.