Transient receptor potential (TRP) channels are a superfamily of functionally versatile cation-permeant ion channels present in almost all mammalian cell types. Although they were initially proposed as store-operated calcium channels, recent progress shows that they exhibit a variety of regulatory and functional themes. Here, we summarize the most salient features of TRP channels, the approaches that are providing meaningful discoveries, and the challenges ahead. We primarily emphasize the understanding gleaned from mouse models engineered to be deficient in various members of TRP superfamily and from the human patients that suffer clinically due to defects in TRP channels.