Vasopressin is a peptide hormone synthesized by neurons of the supraoptic and paraventricular nuclei, which project axon terminals to the neurohypophysis. Consistent with its antidiuretic properties, vasopressin release rises as a function of plasma osmolality, a response that results from accelerated action potential discharge. Previous studies have shown that increases in fluid osmolality depolarize supraoptic neurons in the absence of synaptic transmission, suggesting that these cells behave as intrinsic osmoreceptors. The mechanism by which changes in osmolality are transduced into an electrical signal is unknown, however. Here we report that changes in cell volume accompany physiological variations in fluid osmolality and that these modulate the activity of mechanosensitive cation channels in a way that is consistent with the macroscopic regulation of membrane voltage and action potential discharge. These findings define a function for stretch-inactivated channels in mammalian central neurons.