A better understanding of the mammalian thermoregulatory system may lead to new therapeutic strategies for the treatment of conditions associated with hyperthermia such as infection, drug abuse, and stroke. Classical studies identified the preoptic area (POA) of the anterior hypothalamus as the principal site of mammalian thermoregulation. This region is postulated to contain "warm-sensitive" neurons that are activated by environmental heat and in response trigger an array of autonomic and behavioral responses that restore temperature homeostasis. An extensive scientific literature accumulated over the past 75 years has supported the existence and importance of these warm-sensitive cells, yet their neurochemical identity remains unknown. For this reason key components of the mammalian thermoregulatory circuit have remained inaccessible to modern genetically-targeted approaches in neuroscience. Recently we have used an approach for activity- based RNA sequencing to identify molecular markers that selectively label these long-sought warm-sensitive cells. We have shown using cell-type-specific optogenetic manipulations that activation of these neurons inhibits brown adipose tissue thermogenesis and lowers body temperature. We have also recorded the activity of these neurons in awake behaving mice and shown that they are activated by ambient heat and inhibited by ambient cold. Thus we have identified a novel, molecularly-defined neural population that functionally resembles the long-sought warm-sensitive cells of the POA. We propose here to apply approaches for genetic and projection-targeted neural manipulation and recording to elucidate the downstream circuit by which these cells control behavioral and autonomic thermoregulation.