An important clinical endpoint in patients with cancer is formation of metastases in the brain. Understanding this phenomenon is important in several types of malignancies, including melanoma, lung and breast cancers. Metastatic tumor cells use specific adhesion molecules to home to brain, and there they must attach to microvessel endothelial cells and respond to brain endothelial cell-derived motility factors and brain invasion factors to invade the CNS. Neurotrophins are important invasion factors in this process, and the ability to invade into the brain may well depend on metastatic cell responses to neurotrophins and production of basement membrane-degradative enzymes capable of locally destroying the blood-brain barrier. Brain-metastatic human melanoma cells express low-affinity p75 receptor for neurotrophins such as nerve growth factor, but they do not express the high-affinity-type receptors for nerve growth factor encoded by the protooncogene trkA. Tumor cells can proliferate in the CNS in response to local paracrine growth factors and inhibitors, but their growth also depends on their producing and responding to autocrine growth factors. A major organ-derived (paracrine) growth factor has been isolated that differentially stimulates the growth of cells metastatic to the brain. Characterization of this mitogen demonstrated that it is a transferrin-like glycoprotein; cells that are metastatic to brain express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to other sites. Transferrin-like factors are expressed in fetal brain and could represent the transferrin-like factors that stimulate growth of brain-metastatic melanoma and breast cancer cells. These and other factors are probably important in determining whether metastatic cells can successfully invade, colonize, and grow in the CNS.