The treatment of metastatic breast cancer continues to be a challenging area for medical oncologists. Breast tumors are classified into several groups based on immunohistochemistry: those that are estrogen-receptor–positive and human epidermal growth factor receptor 2 (HER2)-negative; those that are HER2-positive and either estrogen-receptor–positive or estrogen-receptor–negative; and those that are negative for the estrogen receptor, progesterone receptor, and HER2 (known as triple-negative). These biologic factors are an important component of the risk assessment and treatment strategy. Management goals for advanced disease are to target treatment to the specific biology in a more effective way, and to add in targeted agents that may improve the effectiveness of standard therapies, such as hormone therapy and chemotherapy. There are several new therapies that are changing outcome for patients with metastatic disease, such as eribulin, pertuzumab, and ado-trastuzumab emtansine. It is critical to understand the appropriate dosing schedules of novel agents and how best to combine them with standard therapy. Ongoing clinical trials are evaluating new treatment approaches, as well as ways to identify biologic subsets that might benefit from particular therapies. Investigational agents include glembatumumab vedotin, neratinib, and margetuximab.