Prolactin-releasing peptide (PrRP) was first isolated from bovine hypothalamus as an orphan G-protein-coupled receptor using the strategy of reverse pharmacology. PrRP is expressed specifically in the human pituitary and is identified in the hypothalamus as a potent prolactin-releasing factor (PRF) for anterior pituitary cells. The initial studies showed that PrRP was a potent and specific prolactin-releasing factor; however our studies in the pituitary demonstrated that PrRP is more important such as modulator of prolactin release mediated by thyroid-releasing hormone (TRH) than PRF itself. However, physiological studies indicated that PrRP might play a wide range of roles in neuroendocrinology other than prolactin release, i.e., sleep regulation, metabolic homeostasis, food intake, stress responses or cardiovascular regulation. Over 150 papers and several patents have been published on this subject since its initial discovery in 1998. Herein, I review the state of current knowledge of the PrRP system, especially its roles in brain functions and implications for therapy.