We have used gene targeting to examine the role of the G alpha subunit, G(olf), in olfactory signal transduction. Mice homozygous for a null mutation in G(olf) show a striking reduction in the electrophysiological response of primary olfactory sensory neurons to a wide variety of odors. Despite this profound diminution in response to odors, the topographic map of primary sensory projections to the olfactory bulb remains unaltered in G(olf) mutants. Greater than 75% of the G(olf) mutant mice are unable to nurse and die within 2 days after birth. Rare surviving homozygotes mate and are fertile, but mutant females exhibit inadequate maternal behaviors. Surviving homozygous mutant mice also exhibit hyperactive behaviors. These behavioral phenotypes, taken together with the patterns of G(olf) expression, suggest that G(olf) is required for olfactory signal transduction and may also function as an essential signaling molecule more centrally in the brain.