The mechanistic basis of a metastatic cell's ability to proliferate in the parenchyma of certain organs and develop organ-specific metastases is under intense investigation. Signals from paracrine or autocrine pathways, alone or in combination, may regulate tumor cell proliferation with the eventual outcome dependent on the net balance of stimulatory and inhibitory factors. This article summarizes recent reports from our laboratory and others demonstrating that the organ microenvironment can profoundly influence the pattern of gene expression and the biological phenotype of metastatic tumor cells, including induction of melanocyte stimulating hormone receptor and production of melanin, regulation of terminal differentiation and apoptosis, resistance to chemotherapy, and regulation of growth at the organ-specific metastatic site. These recent data from both murine and human tumor models support the concept that the microenvironment of different organs can influence the pattern of gene expression and hence the phenotype of tumor cells at different steps of the metastatic process. These findings have obvious implications for the therapy of neoplasms in general and metastases in particular.