Treatment selection for metastatic breast cancer (MBC) is guided by multiple factors, most importantly hormone receptor (HR) or HER2 expression, treatment history, and prognostic factors such as short disease-free interval, presence of visceral metastases, performance status, and degree of symptoms. Chemotherapy is indicated as initial therapy for patients with HR-negative disease and following failure of hormonal therapies in HR-positive disease. Patients treated with an anthracycline or a taxane in early-stage settings may no longer be candidates for those drugs in MBC, thus underscoring the need for alternative options. Sequential single-agent therapy or combination therapy are viable strategies. Trials have shown that ixabepilone plus capecitabine significantly improves progression-free survival compared with capecitabine alone in anthracycline- or taxane-pretreated or -resistant patients, and single-agent eribulin improves survival compared with the physician's choice of treatment in patients treated previously with at least two regimens for MBC. Regardless of the regimen, proactive management to detect treatment-related adverse events in a timely manner remains important for ensuring effective delivery of treatment. Many promising investigational agents are in development, including T-DM1 (trastuzumab emtansine) and pertuzumab for HER2-positive disease, as well as PARP-1 (poly[adenosine diphosphate ribose] polymerase-1) inhibitors and cetuximab for triple-negative disease. In addition, new options for the treatment of MBC following failure of an anthracycline and a taxane promise to improve patient outcomes. Nurses should remain vigilant for adverse events and remember that the goal of treatment remains control of the disease and palliation.