Approximately 20% of breast cancer demonstrates amplification of the HER2 gene resulting in overexpression of the HER2 protein on the cell surface. Effective targeting with anti-HER2 monoclonal antibodies (trastuzumab, pertuzumab, trastuzumab-emtansine) and tyrosine kinase inhibitors (lapatinib) dramatically improves the natural history of this aggressive disease. Patients with HER2-overexpressing breast cancer (HER2+) achieve higher rates of pathologic complete response (pCR) to cytotoxic chemotherapy and HER2-targeted therapy in neoadjuvant trials compared with less aggressive subtypes. Moreover, a trend toward a positive correlation between pCR and improved long-term survival appears to be emerging in neoadjuvant clinical trials. This article reviews the various definitions of pCR as an end point in neoadjuvant clinical trials and summarizes the use of anti-HER2-targeted agents in the neoadjuvant setting for HER2+ disease.