Temperature-sensitive Transient Receptor Potential Vanilloid ion channel subtypes 1-4 (thermoTRPV1-4) play important roles in a wide range of physiological processes, including temperature sensing and body temperature regulation, inflammation, pain, itch, maintenance of skin, bone and hair and osmotic regulation. ThermoTRPV function is modulated by numerous natural product compounds, such as capsaicin, camphor and cannabinoids. Because of their physiological importance and their druggability, these channels have made attractive potential targets for drug development. Since the beginning of the cryo-EM "resolution revolution" a lot of progress has been made towards dissecting the activation mechanisms of thermoTRPVs and mapping the binding sites for modulatory compounds. Here we review the thermoTRPV physiology and pharmacology and summarize the current knowledge of their mechanisms of gating and ligand binding sites.