Detection of courtship-activating female pheromones by contact chemoreceptors on the front legs of male Drosophila melanogaster is thought to play an important role in triggering courtship behavior. However, the chemosensory organs, cells, and molecules responsible are not known. We have isolated two genes, CheA29a and CheB42a, expressed in nonneuronal auxiliary cells within two nested subsets of chemosensory sensilla on the front legs of sexually mature, adult males. The proteins encoded by the CheA29a and CheB42a genes have no sequence similarity to each other or any other known protein, but they belong to two novel families of proteins encoded by the D. melanogaster genome. Members of the two families are predicted to have a single transmembrane domain at their amino terminus, probably to serve as a signal peptide, suggesting that they are soluble and secreted. Finally, in addition to CheA29a and CheB42a, other genes within each family are expressed preferentially in appendages where chemosensory organs are concentrated, in several cases in a male-specific manner. Our data suggest that CheA29a and CheB42a and other members of these two protein families are involved in male-specific chemical senses, perhaps pheromone response.