A host of endocrine-related pathologies require suppression of the reproductive axis for their successful treatment, including endometriosis, precocial puberty, and sex steroid-responsive cancers (e.g. breast and prostate cancer). Given the prevalence of these health concerns, it is imperative that pharmacological targets of reproductive axis control are investigated and clinical implications considered. To date, it has been challenging to develop a selective, long-acting GnRH antagonist for the treatment of such patients. As a result, individuals are typically treated with a GnRH agonist, a ministration that initially leads to overstimulation of the reproductive axis, followed by its eventual suppression through negative feedback and pituitary GnRH receptor down-regulation. Although effective in the long term, such treatments initially result in flare-ups where symptoms worsen and a multitude of adverse side effects result. Consequently, basic research aimed at identifying suitable targets for reproductive axis inhibition represents an important area of inquiry. One such candidate neuropeptidgeric system is RFamiderelated peptide (RFRP), the mammalian homolog of avian gonadotropin-inhibitory hormone (GnIH). In 2000, Tsutsui and colleagues (1) isolated a hypothalamic dodecapeptide that directly inhibited gonadotropin release in cultured quail pituitary and named this neurochemical GnIH. In birds, GnIH cell bodies are located principally in the paraventricular nucleus of the hypothalamus, with dense projections throughout the brain (2, 3). Additionally, GnIH fibers are in close proximity to GnRH cell bodies with fibers projecting to the median eminence, suggesting potential regulation at both loci (2, 4). A role of the mammalian homolog, RFRP, was later suggested in rodents, with RFRP cell bodies clustered in the dorsomedial hypothalamus, projections upon GnRH neurons and to the median eminence, and pharmacological treatment leading to suppressed LH secretion (5). These findings suggested a conserved role for this peptide across vertebrate species. Indeed, RFRP homologs have been localized to the hypothalamus of all mammalian species studied to date, including hamsters (5–7), rats (5, 8), mice (5, 9), sheep (10– 12), macaques (13), and humans (14). Across species, the consequences of RFRP administration, and the general pattern of perikarya and fiber distribution, suggest a common functional role. To date, the role of RFRP has been explored principally using immunohistochemistry and in situ hybridization or through administration of the peptide followed by measures of hormone secretion and/or GnRH activity. However, to fully characterize the function of RFRP and survey its role in reproductive axis control, it is necessary to observe the consequences of RFRP receptor blockade. To date, such a strategy was not possible, because a selective receptor antagonist was not available. In this issue of Endocrinology, Pineda et al. (15) describe an elegant and comprehensive series of experiments investigating the role of RFRP using a selective antagonist (RF9) of RFRP and a related peptide in the same family, neuropeptide FF. Importantly, neuropeptide FF has not been implicated in regulation of gonadotropin secretion (Pineda, R., and M. Tena-Sempere, unpublished observations), suggesting that effects of RF9 are likely mediated through blockade