Approximately 20% of all breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). Targeting breast cancer through this vital oncogenic protein has been a major step towards improved patient outcomes. Today, several anti-HER2 agents are in clinical use including: the monoclonal antibodies trastuzumab and pertuzumab; the small molecule inhibitors lapatinib, neratinib, and tucatinib; and the antibody–drug conjugates ado-trastuzumab emtansine and trastuzumab deruxtecan, in some jurisdictions. In addition, several trastuzumab biosimilars have recently been granted regulatory approval in North America and the EU, and are enhancing patient access to HER2-directed therapy. The various agents differ greatly in their side-effect profiles and approved indications, from neoadjuvant and adjuvant use in early disease, to first- and later-line use in metastatic disease. This review discusses the current treatment recommendations for the use of anti-HER2 agents alone and in combination, examines the latest advances in HER2-targeted drugs and how they may be best applied in clinical practice, and provides guidance on optimal sequencing of the growing array of therapeutic options for HER2-positive breast cancer.