Human epidermal growth factor receptor 2 (HER2) oncogene addiction has led to the development of anti-HER2 therapies which have revolutionized the management of patients with HER2-positive cancers, with trastuzumab being the cornerstone of treatment of HER2-positive breast cancer. Despite the success of these biologics in breast cancer patients, not all patients with HER2-positive tumors respond to treatment, and many eventually develop resistance to therapy. Developing therapies that that circumvent current resistance mechanisms and improve patient outcomes further remains an area of unmet clinical need. Based on insights gained from established anti-HER2 therapies and our understanding of known resistance mechanisms a number of novel anti-HER2 treatments are being developed. These include novel HER2 antibody-drug conjugates that have shown activity in HER2 high and low tumors, novel HER2 antibodies, T cell bispecific antibodies, and HER2 antibodies in combination with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, immunotherapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. In this article, we review resistance mechanisms to approved HER2 antibodies and provide an overview of emerging therapeutic agents.