Transient receptor potential vanilloid 4 (TRPV4) was identified as the mammalian homologue of the Caenorhabditis elegans osmosensory channel protein, OSM-9. In mammals, TRPV4 is activated by a variety of stimuli including thermal stress, fatty acid metabolites, and hypotonicity. Two distinct mechanisms have been described through which TRPV4 may be activated by hypotonicity: one involves the Src family of nonreceptor protein tyrosine kinases, whereas a second is mediated via arachidonic acid metabolites. TRPV4 likely plays a role in systemic osmoregulation; accordingly, it is expressed in the blood-brain barrier-deficient osmosensory nuclei of the hypothalamus. TRPV4 is also abundantly expressed in the kidney, and its precisely demarcated distribution along the kidney tubule permits speculation about a physiological role in this tissue. TRPV4-expressing and TRPV4-negative tubule segments co-exist at all levels of the kidney, from the cortex through the inner medulla. It is conceivable that basolaterally expressed TRPV4 transmits signals arising in the interstitium (e.g, changing tonicity) to more-distal tubule segments where "fine-tuning" of the incipient urine takes place.