In 2003, two independent groups of researchers discovered almost simultaneously that inactivating mutations of the G protein coupled receptor, GPR54, cause hypogonadotropic hypogonadism in mice and men. Since this discovery, kisspeptins, the natural ligands for GPR54, have been thrust into the reproductive neuroendocrine spotlight, as major regulators of GnRH function. Kisspeptins are the peptide products of the KiSS-1 gene, and potently stimulate gonadotrophin secretion when administered either centrally or peripherally. Expression of KiSS-1 has been localised to specific regions of the hypothalamus in many species and is regulated by gonadal steroids and across the estrous cycle. It appears that kisspeptin transmits steroid feedback signals to GnRH cells, especially the positive feedback effect of estrogen that causes the preovulatory GnRH/LH surge. Importantly, kisspeptin function appears to be fundamental to the initiation of puberty.