The structure and the function of the Hypothalamus-Pituitary- Gonadal (HPG) axis is an integral part of the knowledge on the physiology of the human body that every bioscientist receives during his/her education. Especially for those scientists who work in the fields of assisted reproduction and endocrinology, the function of HPG axis is of paramount importance. The HPG axis drives reproduction: Hypothalamus secretes Gonadotrophin Releasing Hormone (GnRH), GnRH stimulates the gonadotroph cells of pituitary to secrete Follicular Stimulating Hormone (FSH) and Luteinizing Hormone (LH) and in turn these two hormones regulate the gonadal function in both sexes. Steroid hormones as well as inhibins and activins, produced by gonads, influence the secretion of gonadotrophins. It is also well known that internal and external cues influence the HPG axis. For example, stress hormones, leptin and the opioid system modulate the secretion of GnRH and gonadotrophins. However, it has become obvious that they are not main regulators. GnRH, FSH and LH, androgens, and oestrogens are the main players in this classical schema and until recently, GnRH was recognized as the neurohormone having the pivotal role in the physiology of reproduction. This is the basic knowledge on the function of HPG axis. However, during the last ten years, novel findings on the actions of RFamide peptides have challenged this knowledge. RFamides are small peptides possessing the motif Arg-Phe-NH2 at C-terminus. Two groups of RFamide peptides proved to participate in HPG axis: Gonadotropin Inhibiting Hormone (GnIH) and its related peptides and the group of kisspeptins.