HER2, is a member of the ErbB family of receptor tyrosine kinases, that plays a key role in the pathogenesis of breast cancer, and when overexpressed, can correlate with a particularly aggressive clinical phenotype. It is estimated in roughly 18 to 20% of breast cancer patients, there is amplification of the HER2 gene resulting in aberrant overexpression of p185HER2 protein. As such, HER2 represents an attractive therapeutic target. In this review, we explore the clinical evolution of trastuzumab, a humanized monoclonal antibody with high specificity and affinity for the HER2 extracellular domain, and additionally examine more recent efforts targeting the intracellular tyrosine kinase domain of HER2 using small molecule tyrosine kinase inhibitors.