Recent years have seen great advances in the molecular description of sensory neurobiology. Of the five popularly characterized senses – sight, hearing, taste, smell, and touch – touch is among the most varied and least understood. Within this modality is the ability to sense mechanical forces, chemical stimuli, and temperature, and the molecules that mediate this ability have been a long-standing mystery. Categorized according to their mechanism of gating, ion channels can be activated by signals such as specific ligands, voltage, or mechanical force. Another type of signal, temperatures above 43oC, was shown to activate the ion channel TRPV1 (VR1), a member of Transient Receptor Potential (TRP) family of cation channels. These high temperatures are perceived as painful or noxious by many organisms. Interestingly, TRPV1 is also activated by capsaicin, the active ingredient of chili peppers. A second TRP, TRPV2 (VRL1) was soon found to respond to yet higher temperatures (53oC). Building on these initial findings, my lab focused on identifying additional temperature-activated ion channels. Although other members of the TRP family of channels were not known to have thermosensing roles when we started this project three years ago, we postulated that novel members were likely to be functionally related to TRPV1 and TRPV2. Taking advantage of the ongoing human genome project, we mined for additional TRP channels. The next step was to systematically screen these new TRPs for expression in tissues relevant for temperature sensation and to assay the activity of these channels in heterologous systems either by imaging intracellular calcium levels or by electrophysiology. As hoped, our work has led to the characterization of a novel warm-activated TRP channel, TRPV3 (33oC threshold) and two novel cold-activated TRP channels, TRPM8 (25oC threshold) and ANKTM1 (17oC threshold). TRPM8 is also the receptor for the compound menthol, providing a molecular explanation of why mint flavors are typically perceived as refreshingly cooling. Together these temperature-activated channels represent a new sub-family of TRP channels that we have dubbed thermoTRPs. The remarkable ability of the thermoTRPs to confer temperature sensitivity to a variety of cell types suggests that they are either direct sensors of temperature or are activated via a ubiquitous temperature-activated signaling mechanism. In agreement with a role in initiating temperature sensation, most of the thermoTRPs are normally found in subsets of Dorsal Root Ganglia (DRG) neurons. These sensory neurons convey information about the environment through specialized neurites that extend to the skin from cell bodies in the vertebral column. In fact, a single DRG neuron nerve ending marks a small spot (<1mm in diameter) on the skin surface that often senses a narrow range of temperature stimuli. Recording directly from DRG nerve fibers has helped classify some of these neurons as hot-, warm-, or cool-responsive. Still other neurons, called polymodal nociceptors, sense noxious thermal (cold and hot) and mechanical stimuli. These physiological studies strikingly correlate with results of our detailed expression analysis of the thermoTRPs in DRG neurons. We have found neurons that express only TRPV1, only TRPM8, or both TRPV1 and ANKTM1. However, a surprisingly distinct expression pattern was observed for TRPV3, the warm receptor. High levels of TRPV3 are only observed in skin keratinocytes in the mouse, suggesting that skin cells might be able to “sense” temperature and then communicate this information to DRG neurons. How temperature information is coded from the skin to the spinal cord and brain is not well understood. The need for thermosensation exists in all organisms. Therefore we have asked whether non-vertebrates also use thermoTRPs to sense temperature. We have recently shown that the Drosophila sequence orthologue of ANKTM1 is an ion channel activated by warm temperatures, suggesting an evolutionary conserved role of TRP channels in temperature sensing. This leads to the question of whether all temperature-activated ion channels are members of the TRP family. Conversely, not all TRPs are thermosensitive. However, a wide-ranging set of experiments in different species points to a recurring role of TRP channels in diverse sensory functions. By identifying the proteins that likely initiate the molecular cascade leading to temperature perception, we now have the opportunity not only to probe the basic foundation of our sense of temperature but to extend these insights into important areas of human health such as pain pathophysiology.