Several transient receptor potential channels were recently found to be activated by temperature stimuli in vitro. Their physiological and behavioral roles are largely unknown. From a temperature-preference behavior screen of 27,000 Drosophila melanogaster P-insertion mutants, we isolated a gene, named pyrexia (pyx), encoding a new transient receptor potential channel. Pyx was opened by temperatures above 40 degrees C in Xenopus laevis oocytes and HEK293T cells. It was ubiquitously expressed along the dendrites of a subset of peripheral nervous system neurons and was more permeable to K(+) than to Na(+). Although some pyx alleles resulted in abnormal temperature preferences, pyx null flies did not have significantly different temperature preferences than wild-type flies. But 60% of pyx null flies were paralyzed within 3 min of exposure to 40 degrees C, whereas only 9% of wild-type flies were paralyzed by the same stimulus. From these findings, we propose that the primary in vivo role of Pyx is to protect flies from high-temperature stress.