The pathogenesis of metastasis depends on the interaction of unique tumor cells (“seed”) with specific host organ microenvironment (“soil”). In fact, metastases develop and survive because tumor cells usurp homeostatic mechanisms. A prime example is brain metastasis. Brain metastases and glioblastoma are densely surrounded and infiltrated by activated astrocytes expressing glial fibrillary acidic protein. The role of astrocytes is to support the function and viability of neurons, and we therefore questioned whether astrocytes can also protect tumor cells from cytotoxic drugs. Astrocytes cocultured with tumor cells established a gap-junction communication network and protected the tumor cells from all tested chemotherapeutic drugs. We have identified the signal that astrocytes send to tumor cells as endothelin-1, -2. Phosphorylation of endothelin receptors A and B on tumor cells was followed by activation of Akt, MAPK, and upregulation of survival genes in tumor cells. Luciferase-tagged breast cancer, lung cancer, and glioblastoma cells were implanted in the brains of nude mice. Administration of the dual endothelin receptor inhibitor Macitentan® combined with Taxotere or Temozolomide produced complete destruction of established metastasis and glioblastoma in nude mice. These data clearly demonstrate that astrocytes influence the biological behavior of tumor cells in the brain and reinforce the conclusion that the organ microenvironment must be taken into consideration for the design of effective therapy. The studies described here began with a hypothesis that astrocytes protect tumor cells from cytotoxic agents. In vitro studies using cocultures of astrocytes and tumor cells were followed by successful in vivo therapy studies. These translational studies stimulated ongoing phase I clinical trials of glioblastoma.