Odorant stimulation leads to a depolarization of olfactory receptor neurons. A mechanism underlying this transduction, which occurs in the sensory cilia, involves a G-protein-mediated increase in adenylyl cyclase activity, and therefore a rise in internal cyclic AMP and consequent opening of a cAMP-gated cation channel on the plasma membrane. Another mechanism, not as well established, involves the opening of an inositol trisphosphate-activated cation channel on the plasma membrane as a result of phospholipase C activity. In both cases, an influx of cations is thought to generate the depolarizing receptor potential. We now report, however, that the mechanism is actually more complex. The odorant-induced current appears to contain an inward chloride component also, which is triggered by calcium influx through the cation-selective channel. This newly found chloride component can be as large as the cationic component. The co-existence of cationic and chloride components in the odorant response, possibly unique among sensory transduction mechanisms, may serve to reduce variations in the transduction current resulting from changes in external ionic concentrations around the olfactory cilia. Our finding can explain the long-standing puzzle of why removal of most mucosal cations still does not diminish the amplitude of the olfactory receptor cell response.