The heterotrimeric G-protein G(s) couples cell-surface receptors to the activation of adenylyl cyclases and cyclic AMP production (reviewed in refs 1, 2). RGS proteins, which act as GTPase-activating proteins (GAPs) for the G-protein alpha -subunits alpha (i) and alpha (q), lack such activity for alpha (s) (refs 3-6). But several RGS proteins inhibit cAMP production by G(s)-linked receptors(7,8). Here we report that RGS2 reduces cAMP production by odorant-stimulated olfactory epithelium membranes, in which the alpha (s) family member alpha (olf) links odorant receptors to adenylyl cyclase activation(9,10). Unexpectedly, RGS2 reduces odorant-elicited cAMP production, not by acting on alpha (olf) but by inhibiting the activity of adenylyl cyclase type III, the predominant adenylyl cyclase isoform in olfactory neurons. Furthermore, whole-cell voltage clamp recordings of odorant-stimulated olfactory neurons indicate that endogenous RGS2 negatively regulates odorant-evoked intracellular signalling. These results reveal a mechanism for controlling the activities of adenylyl cyclases, which probably contributes to the ability of olfactory neurons to discriminate odours.