Transient receptor potential vanilloid-3 (TRPV3) is a Ca(2+)-permeable nonselective cation channel widely expressed in skin keratinocytes, as well as oral and nasal epithelia. TRPV3 is activated by innocuous warm as well as noxious hot temperatures. Activation of TRPV3 in skin keratinocytes causes release of multiple substances, which in turn regulate diverse functions including skin barrier formation, hair growth, wound healing, temperature sensing, and itch and pain perceptions. While several natural and synthetic ligands have been described for TRPV3, only one of them, farnesyl pyrophosphate, is naturally produced in animal cells. Together with the use of genetic mouse models, applications of these compounds have revealed not only the physiological functions but also regulatory mechanisms of TRPV3 channel by extracellular Ca(2+), Mg(2+), and protons as well as intracellular Ca(2+)-calmodulin, ATP, phosphatidylinositol 4,5-bisphosphate, polyunsaturated fatty acids, protons, and Mg(2+). Gain-of-function genetic mutations of TRPV3 in rodents and humans have been instrumental in unveiling the critical role of this channel in skin health and disease.