The activity of the hypothalamo-pituitary-gonadal axis involves the release of gonadotrophin-releasing hormone (GnRH) into the portal blood system, subsequently stimulating the release of gonadotrophins, luteinising hormone (LH) and follicle-stimulating hormone (FSH). In turn, gonadotrophins act on the gonads to regulate reproductive activity. Characterisation of GnRH neuron regulators has significantly progressed in recent years. In 2000 the RFamide-related peptide (rfrp) gene was identified in humans and shown to produce two peptides, RFRP-1 and RFRP-3. Rfrp is the mammalian ortholog of avian gonadotrophin-inhibitory hormone (gnih), which was shown to inhibit gonadotrophin release from quail pituitaries. This finding spurred great interest in the roles of RFRP peptides, and especially RFRP-3, in the regulation of endocrine functions in mammals. A large number of studies have since then aimed at determining the involvement of RFRP-3 in the regulation of the reproductive function and suggest that the effect of the peptide on the gonadotrophic axis may vary according to species, gender and physiological states. This review comprehensively summarises the variable effects of RFRP-3 that are observed on the mammalian reproductive function.