Orphan receptor GPR103, a pyroglutamylated RFamide peptide receptor (QRFPR), is a class A G protein-coupled receptor (GPCR) and it is coupled to a Gi alpha subunit (Gi/0) and/or to a Gq protein. Synteny analysis revealed the existence of paralogous genes of QRFPR in mouse, zebrafish and coelacanth. These paralogous genes emerged along with species-specific gene or genome duplications that occurred during vertebrate evolution. 26RFa/QRFP is the high-affinity endogenous ligand for QRFPR and in fish it has been suggested as an orexigenic action of 26RFa/QRFP. The structure, tissue-specific expression and biochemical activity of the 26RFa/QRFP–QRFPR system are conserved across the Chordata phylum, from fish to mammals. In order to study the molecular evolution of mammal QRFPR, we searched for the presence of natural selection on the qrfpr genes using a bioinformatic approach. Overall, the results clearly indicate that mammal QRFPRs are under positive selection, but the majority of positively selected amino acids did not alter the biochemical properties of these proteins.