The range of systemic therapy options for patients with HER2-positive breast cancer has expanded dramatically since the introduction of trastuzumab in the late 1990’s. Physicians are now faced with a broad range of therapeutic options, and a key challenge is determining which agent(s) to use in any given clinical situation. In this presentation, I will review clinical trial data and hence suggest “gold standards” for the management of HER2-positive breast cancer. I will also discuss scenarios in which deviation from these guidelines might be appropriate.