In signal transduction of metazoan cells, ion channels of the family of transient receptor potential (TRP) have been identified to respond to diverse external and internal stimuli, among them osmotic stimuli. This review highlights a specific member of the TRPV subfamily, the TRPV4 channel, initially named vanilloid-receptor related osmotically activated channel (VR-OAC) or OTRPC4. In a striking example of evolutionary conservation of function, mammalian TRPV4 has been found to rescue osmo- and mechanosensory deficits of the TRPV mutant strain osm-9 in Caenorhabditis elegans. This is an astounding finding given the <26% orthology between OSM-9 and TRPV4 proteins. Here, recent findings pertaining to TRPV4's mechano- and osmosensory function in endothelia, in the alveolar unit of the lung, and in intestinal sensory innervation are reviewed, namely, transduction of mechanical shear stress in endothelia, maintenance of alveolar integrity on the endothelial side, and intestinal mechanosensation of noxious stimuli by dorsal root ganglion sensory neurons, which can be potently sensitized to mechanical stimuli by activation of the proteinase-activated receptor 2 (PAR-2), in a strictly TRPV4-dependent manner.