Brain metastases are a common complication of cancer and continue to be associated with a poor prognosis. Management of brain metastases typically requires a multidisciplinary approach which may include whole-brain radiation therapy, stereotactic radiosurgery, surgery, and systemic therapy. Historically, the use of systemic therapy in brain metastases has been challenging because of the resistance to conventional chemotherapies secondary to the blood-brain barrier and an often heavily pre-treated patient population, and the paucity of well-conducted randomized trials in these heterogeneous patient populations. Newer agents, including immunotherapy and targeted therapies, are playing increasingly important roles in the up-front management of brain metastases. In this overview, we review recent advances in systemic therapies for brain metastases and the evidence supporting their use in this patient population.