The year 2007 marks exactly two decades since human epidermal growth factor receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer (Slamon et al., 1987). This finding established the HER2 oncogene hypothesis for the development of some human cancers. An abundance of experimental evidence compiled over the past two decades now solidly supports the HER2 oncogene hypothesis. A direct consequence of this hypothesis was the promise that inhibitors of oncogenic HER2 would be highly effective treatments for HER2-driven cancers. This treatment hypothesis has led to the development and widespread use of anti-HER2 antibodies (trastuzumab) in clinical management resulting in significantly improved clinical antitumor efficacies that have transformed the clinical practice of oncology. In the shadows of this irrefutable clinical success, scientific studies have not yet been able to mechanistically validate that trastuzumab inhibits oncogenic HER2 function and it remains possible that the current clinical advances are a consequence of the oncogene hypothesis, but not a translation of it. These looming scientific uncertainties suggest that the full promise of the treatment hypothesis may not yet have been realized. The coming decade will see a second generation of HER2-targeting agents brought into clinical testing and a renewed attempt to treat HER2-driven cancers through the inactivation of HER2. Here, I review the development of treatments that target HER2 in the context of the HER2 oncogene hypothesis, and where we stand with regards to the clinical translation of the HER2 oncogene hypothesis.