It is estimated that 10% to 30% of patients with solid tumors are diagnosed with central nervous system (CNS) metastasis. Common primary sites include lung, breast, melanoma, kidney, and colorectal. Brain metastases are increasing, due to the aging population, detection of subclinical disease, and control of systemic disease. CNS metastases are a major cause of morbidity and mortality affecting survival, neurocognition, speech, coordination, behavior, and quality of life. In pediatric acute lymphocytic leukemia event-free survival rates are >80% and the CNS is an important source of extramedullary relapse. CNS metastases are an increasing problem in solid tumors. In this CCR Focus series, four main topics are reviewed: (a) HER-2-positive breast cancer as a paradigm for the problem; (b) model systems for brain metastasis and mechanistic insights into the pathogenesis of brain metastasis; (c) the unique physiology of the blood brain barrier; (d) and the evolving role of radiotherapy in CNS disease and strategies to improve the therapeutic index. Areas for future research include the need for an understanding of site-specific metastasis, effective anticancer strategies for sanctuary sites, assays to detect drug accumulation in sanctuary sites, prevention of CNS metastasis, improving the therapeutic ratio of systemic and CNS-directed therapies, behavioral tools for anticipating/measuring long-term neurocognitive defects, and quality of life assessment of the long-term effect of systemic and CNS-directed therapies.