Endothelin (ET) is a potent autocrine mitogen produced by reactive and neoplastic astrocytes. ET has been implicated in the induction of astrocyte proliferation and other transformations engendered by brain pathology, and in promoting the malignant behavior of astrocytomas. Reactive astrocytes containing ET are found in the periphery/penumbra of a wide array of CNS pathologies. Virtually all brain pathology deforms the surrounding parenchyma, either by direct mass effect or edema. Mechanical stress is a well established stimulus for ET production and release by other cell types, but has not been well studied in the brain. However, numerous studies have illustrated that astrocytes can sense mechanical stress and translate it into chemical messages. Furthermore, the ubiquitous reticular meshwork formed by interconnected astrocytes provides an ideal morphology for sensing and responding to mechanical disturbances. We have recently demonstrated stretch-induced ET production by astrocytes in vitro. Inspired by this finding, the purpose of this article is to review the literature on (1) astrocyte mechanosensation, and (2) the endothelin system in astrocytes, and to consider the hypothesis that mechanical induction of the ET system may influence astrocyte functioning in CNS pathophysiology. We conclude by discussing evidence supporting future investigations to determine whether specific inhibition of stretch-activated ion channels may represent a novel strategy for treating or preventing CNS disturbances, as well as the relevance to astrocyte-derived tumors.