Localized to the vestibule of the nasal cavity, neurons of the Grueneberg ganglion (GG) respond to cool ambient temperatures. The molecular mechanisms underlying this thermal response are still elusive. Recently, it has been suggested that cool temperatures may activate a cyclic guanosine monophosphate (cGMP) pathway in the GG, which would be reminiscent of thermosensory neurons in Caenorhabditis elegans. In search for other elements of such a cascade, we have found that the cyclic nucleotide-gated ion channel CNGA3 was strongly expressed in the GG and that expression of CNGA3 was confined to those cells that are responsive to coolness. Further experiments revealed that the response of GG neurons to cool temperatures was significantly reduced in CNGA3-deficient mice compared to wild-type conspecifics. The observation that a cGMP-activated non-selective cation channel significantly contributes to the coolness-evoked response in GG neurons strongly suggests that a cGMP cascade is part of the transduction process.