The routine clinical use of anti-HER2 targeted therapy has radically improved outcomes for patients with HER2-positive breast cancer. Relapse rates after adjuvant therapy are low, and the median overall survival of patients with advanced disease has lengthened significantly. Despite this, metastatic HER2-positive breast cancers almost invariably develop therapeutic resistance, mediated by a variety of biological mechanisms. In this presentation, I will discuss putative molecular mechanisms of therapeutic resistance in HER2-positive breast cancer and describe recent attempts to circumvent them in the clinic.