Ion channels and ionotropic neurotransmitter receptors have long been investigated as the principle targets of inhaled volatile anesthetics (VAs), but emerging evidence suggests that G-protein coupled receptors (GPCRs) might also directly interact with VAs. To survey the extent of interaction between VAs and diverse GPCRs, we have turned to the 1000+ member family of olfactory receptors (ORs), taking advantage of their unique expression pattern of a single OR per neuron. Through optical imaging and electrophysiological recordings, we show that different VAs trigger the normal transduction cascade in distinct subsets of cells in a dose-dependant manner. Together with evidence of antagonism by odorants, this selective activation strongly implicates a direct action of VAs upon particular olfactory receptors. The finding that VAs stimulate nearly 8% of olfactory GPCRs suggests that probing related Class A GPCRs may reveal a pool of VA targets whose altered signaling contributes to anesthetic effects.