Resiniferatoxin, an extremely irritant diterpene present in several members of the genus Euphorbia, produced an 8 C decrease in the rectal temperature of mice with an effective dose in the range of 2-20 micrograms/kg. The structurally related natural product capsaicin produced a similar magnitude of fall in body temperature, albeit with 1000-fold lower potency. Tolerance to the hypothermic effects of both compounds readily developed and cross-tolerance between the compounds was observed. The extreme potency of resiniferatoxin should facilitate biochemical analysis of the mechanism of action of this class of compounds.