Pheromonal activation of the vomeronasal organ (VNO) elicits genetically preprogrammed behaviors and physiological changes in mammals. We have identified a novel gene family encoding over one hundred VNO specific receptors, the V3Rs. V3R sequences are highly similar to each other and appear distantly related to the putative pheromone receptors, V1Rs, and the taste receptors, T2Rs. Within the VNO, V3R-positive neurons are distinct from neurons expressing the pheromone receptor families V1R and V2R. The V3Rs are likely to represent a new large family of pheromone receptors in mammals. Multiple V3R-related human sequences have been identified, including one clone retaining the capacity to create a complete and functional transcript. Our data uncover a striking complexity in the molecular and cellular organization of the VNO and provide an essential framework for the study of pheromone signaling in mammals.