Metastasis to the brain is prevalent in solid tumors and lymphomas, and is associated with shortened survival. The brain is regarded as a sanctuary site for metastatic tumor cells where they exist partially protected from drugs by the blood-tumor barrier. Model systems for brain metastasis have been developed and are now yielding mechanistic insights into the roles of angiogenesis, energy metabolism, the Her-2 and Stat3 signaling pathways, and dormancy. Specific, new approaches to combat brain metastatic disease are needed.Metastasis, the spread of cancer from the site of primary tumor growth to distant organs, is a leading cause of cancer morbidity and mortality. The metastatic process is complex, requiring invasion from the primary tumor, intravasation, survival, arrest and extravasation of the circulatory system and colonization of a distant site (reviewed in refs. 1, 2). In addition to these general requirements, tumor cells may acquire the ability to preferentially colonize certain organs. In theory, organ-specific metastasis may result from (a) tumor cell trapping-tumor cell arrest based on the pattern of blood flow from the primary tumor to the first capillary bed and the ability of the tumor cells to form aggregates; (b) tumor cell adhesion-specific adhesive interactions between tumor cells and the endothelia of certain organs; and/or (c) tumor cell niches-the microenvironment of a distant organ creating a permissive site for metastatic colonization. Molecular factors that may contribute to organspecific metastasis of breast cancer to the lung and bone have been identified by experimental studies from the Massague lab, from lung-and bone-colonizing variants of a human breast carcinoma cell line (3, 4). However, we are not nearly as advanced in our understanding of central nervous system or ''brain'' metastases.Brain metastases occur late in the progression of multiple types of cancer and are associated with poor patient survival.The incidence of brain metastases may be underestimated due to the presence of asymptomatic lesions, a focus on systemic lesions in a seriously ill patient, and incomplete reporting (5). Posner and Chernik reported data from 3,219 cancer patient autopsies conducted from 1970 to 1976. Intracranial, dural, and leptomeningeal lesions were found in 24%, 20%, and 8% of cases, respectively. Intracranial metastases were most prevalent from lung cancer (3.1%), followed by breast cancer (2.9%), melanoma (2.8%), and lymphoma (1.7%); another 4.2% of brain metastases came from primary tumors of unknown histology (6, 7).Recent studies investigating patients with metastatic lung and breast cancer reported alarming rates of brain metastases: among metastatic breast cancer patients with Her-2+ tumors, the incidence of brain metastases varied from 26% to 48% (8 -12). Where examined, the majority of patients were responding to trastuzumab treatment or had systemically stable disease when they developed brain metastases. Omuro et al. (13) followed patients with non -small cell lung carcino...