For nearly 60 years, we have known that the brain plays a pivotal role in regulating the osmolality of body fluids. Over this time period, scientists have determined the structure and function of arginine vasopressin and its receptors, the role of the posterior pituitary as a storage site, and the determinants of vasopressin release. The cellular mechanisms by which the kidney responds to vasopressin are also well understood. One area that remains unclear is the neural mechanisms underlying osmoreception. New findings have implicated the TRPV family of cation channels as osmo-mechanoreceptors that may mediate the neuronal responses to changes in systemic tonicity. This topic is reviewed here.