HER2 is a well-known oncogenic receptor tyrosine kinase. HER2 gene amplification occurs in about 20% of breast cancer (BC), which leads to overexpression of HER2 protein, known as HER2-positive BC. Inhibitors of HER2 have significantly improved the prognosis of patients with this subset of BC. Since 1998, seven HER2 inhibitors have been developed to treat this disease. However, drug resistance is common and remains a major unresolved clinical problem. Patients typically show disease progression after some time on treatment. This review discusses the complexity and diversified nature of HER2 signaling, the mechanisms of actions and therapeutic activities of all HER2 inhibitors, the roles of HER2 and other signaling proteins in HER2-positive BC resistant to the inhibitors, the non-cell-autonomous mechanisms of drug resistance, and the heterogeneity of tumor HER2 expression. The review presents the concept that drug resistance in HER2-positive BC results primarily from the inability of HER2 inhibitors to deplete HER2. Emerging therapeutics that are promising for overcoming drug resistance are also discussed. Copyright © 2020. Published by Elsevier Inc.