Kidneys are complex highly organized paired organs of nearly one million nephrons each. They rigorously process about 180 l of plasma daily to keep whole body homeostasis. To effectively perform such a titanic work, kidneys rely on mechanisms able to sense dynamic changes in composition and flow rates of protourine along the renal tubule. It is envisioned that Ca²⁺-permeable transient receptor potential (TRP) channels, and specifically mechanosensitive TRPV4, can serve to interpret these external mechanical cues in the form of elevated intracellular Ca²⁺ concentration. This, in turn, initiates multiple cellular responses and adaptation mechanisms. The current review summarizes up-to-date knowledge about the sites of TRPV4 expression in renal tissue as well as discusses the functional role of the channel in cellular responses to hypotonicity and tubular flow. We will also provide insights as to how TRPV4 fits into classical polycystin mechanosensory complex in cilia and will speculate about previously underappreciated clinical implication of pharmacological TRPV4 targeting in treatment of polycystic kidney disease.