Vertebrate olfactory receptor neurons(ORNs) transduce odor stimuli into electrical signals by means of an adenylyl cyclase/rncAMP second messenger cascade, but it remains widely debated whether this cAMP cascade mediates transduction for all odorants or rnonly certain odor classes. To address this problem, we have analyzed the generator currents induced by odors that failed to produce rncAMP in previous biochemical assays but instead produced IP(3)(“IP(3)-odors”). We show that in single salamander ORNs,sensory rnresponses to“cAMP-odors” and IP(3)-odors are not mutually exclusive but coexist in the same cells. The currents induced by IP(3)rnodors exhibit identical biophysical properties as those iduced by cAMP odors or direct activation of the cAMP cascade. By disrupting rnadenylyl cyclase to block cAMP formation using two potent antagonists of adenylyl cyclase. SQ22536 and MDL12330A, we show that rnthis molecular step is necessary for the transduction of both odor classes. To assess whether these results are also applicable to mamrnmals,we examine the electrophysiological responses to IP(3)-odors in intact mouse main olfactory epithelium (MOE) by recording rnfield potentials. The results show that inhibition of adenylyl cyclas prevents EOG responses to both oder classes in mouse MOE,even rnwhen “hot spots” with heightened sensitivity to IP(3)-odors are examined.rn