Cell swelling activates or upregulates a number of anion channels. Of the volume-activated or -regulated anion channels (VAACs or VRACs), the volume-sensitive outwardly rectifying anion channel (VSOR) is most prominently activated and ubiquitously expressed. This channel is known to be involved in a variety of physiological processes including cell volume regulation, cell proliferation, differentiation and cell migration as well as cell turnover involving apoptosis. Recent studies have shown that VSOR activity is also involved in a number of pathophysiological processes including the acquisition of cisplatin resistance by cancer cells, ischaemia-reperfusion-induced death of cardiomyocytes and hippocampal neurons, glial necrosis under lactacidosis as well as neuronal necrosis under excitotoxicity. Moreover, VSOR serves as the pathway for glutamate release from astrocytes under ischaemic conditions and when stimulated by bradykinin, an initial mediator of inflammation. So far, many signalling molecules including the EGF receptor, PI3K, Src, PLCgamma and Rho/Rho kinase have been implicated in the regulation of VSOR activity. However, our pharmacological studies suggest that these signals are not essential components of the swelling-induced VSOR activation mechanism even though some of these signals may play permissive or modulatory roles. Molecular identification of VSOR is required to address the question of how cells sense volume expansion and activate VSOR.