Breast cancer is the second leading cause of cancer-related death in women in the United States, and for nearly all with metastatic disease at presentation or relapse it will be incurable. The goals of therapy are to optimize quality of life and, if possible, prolong time to progression of disease and death. For a select group of patients an aggressive surgical approach may be considered. Initial palliation with endocrine therapy should be the primary consideration for patients with metastatic hormone receptor-positive tumors. Cytotoxic chemotherapy is appropriate for those with hormone-refractory disease, rapidly progressive visceral disease, or early relapse after adjuvant therapy. If a tumor overexpresses HER2, targeted treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) is possible. Consequently, accurate determination of the status of these predictive markers in tissue (possibly from a recurrence site) is key. Other novel agents are adding to the wide choices of standard chemotherapies already available. This review offers an approach to the selection of individualized and rational therapies for patients with metastatic breast cancer.