It has been more than 2 decades since the first publication describing the potential role of HER2 in breast cancer. A variety of techniques were employed in the initial studies to assess HER2 at DNA, RNA, and protein levels. These studies, mostly retrospective, demonstrated that HER2 is a marker of poor prognosis and suggested that it may be a predictive marker of response to certain types of chemotherapy. Like hundreds of other biomarkers of potential significance in breast cancer, interest in the clinical use of HER2 remained subdued. The development of a targeted treatment to HER2 and indirectly this pathway (ie, Herceptin [trastuzumab], Genentech, Inc, South San Francisco, California) changed the course of history for HER2. As soon as the clinical trials for Herceptin began, initially in patients with metastatic breast cancer and later in an adjuvant setting, HER2 became a clinically useful biomarker, (1) and it met 1 of the 3 pivotal requirements for biomarker validation, as described by McGuire. (2) The journey to validate HER2 assays has faced several obstacles during nearly one and one-half decades. It has certainly lagged significantly behind estrogen and progesterone receptor assay validation. One would expect that the experiences gained from hormone receptor assay validation would have helped, but that does not seem to be the case. It is fair to say that, at this time, there is no true gold standard for HER2 testing in breast cancer, and if guidelines published by the National Institutes of Health and McGuire (2) are considered, not a single study exists that fully addresses the critical steps needed for such a validation study. These guidelines require 3 important steps: technical validation, clinical validation, and clinical usefulness.