Mammalian gonadotropin-releasing hormone (GnRH D is a hypothalamic decapeptide that stimulates gonadotropic hormone secretion upon interaction with its membrane receptors (type I) on pituitary cells, thereby governing reproductive processes. A second releasing hormone (GnRH IF) expressed in mammals was shown earlier to be expressed in nonmammals and to have its own receptor. Here we demonstrate that a second receptor (type TI) gene is present in the human genome, and report the cloning and characterization of its cDNA from G-protein-coupled/7 transmembrane receptor having a C-terminal cytoplasmic tail; it resembles more closely the type II receptors of amphibians and fish (similar to 55% identity) than it does the type I receptor of humans (similar to 39%). The GnRH type II receptor proved to be experimentally functional with, and specific for, GnRH II, GnRH receptor type II RNA is expressed ubiquitously in human tissues. This is the first report of a GnRH type II receptor in mammals. Its identification will permit exploration of its role in regulating gonadotropin secretion, female sexual behavior, and tumor cell growth.