Human epidermal growth factor receptor 2 (HER2) is over-expressed in 15% – 30% of breast cancers. Women with HER2-positive breast cancer tend to have more aggressive cancer, increased risk of recurrence, and less favorable survival outcomes than women with HER2-negative breast cancer. This review focuses on HER2 and its role in breast cancer pathogenesis. We begin by providing background information on the biological function of HER2 and how this gene contributes to breast cancer development and progression. Next, we review the ongoing debate surrounding the accuracy of available modalities for detecting HER2, namely fluorescence in-situ hybridization (FISH) versus immunohistochemistry (IHC). We include current data examining the relationship between HER2 and possible genetic modifiers, such as topoisomerase IIα, BRCA1, and genomic instability in breast cancer subjects, and how these relationships may influence response to current therapies directed against HER2. We then discuss trastuzumab, a monoclonal antibody used to treat HER2+ breast cancers, and, after providing an overview of the molecular processes involved in targeted therapy, we summarize the current literature regarding outcomes, as well as the potential impact on the overall health of patients, with special attention to cardiac risk involved with such therapy. Finally, we touch on future directions in this field, including newer targeted therapies in development.