HER2 (ErbB2), a member of the HER family of tyrosine kinase receptors (HER1-4), is a major driver of tumor growth in 20% of breast cancers. Treatment with the anti-HER2 monoclonal antibody trastuzumab has revolutionized the outcome of patients with this aggressive breast cancer subtype, but intrinsic and acquired resistance is common. Growing understanding of the biology and complexity of the HER2 signaling network and of potential resistance mechanisms has guided the development of new HER2-targeted agents. Combinations of these drugs to more completely inhibit the HER receptor layer, or combining HER2-targeted agents with agents that target downstream signaling, alternative pathways, or components of the host immune system, are being vigorously investigated in the preclinical and clinical settings. As a result, the list of more effective and well tolerated FDA-approved new regimens for patients with HER2+ tumors is constantly growing.