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 qrfpr paralogous genes in mouse, zebrafish and coelacanth. These paralogous genes emerged along with the species-specific gene or genome duplications that occurred during vertebrate evolution. Neuropeptide 26RFa (also termed QRFP) is the latest member of the RFamide peptide family to be discovered in the hypothalamus of vertebrates. 26RFa/QRFP is a 26-amino acid residue peptide that was originally identified from the frog brain. It has been shown to exert orexigenic activity in mammals and to be a ligand of the previously identified orphan G protein-coupled receptor, QRFPR. 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 fish QRFPRs, we investigated the presence of natural selection on the QRFPR family using a bioinformatic approach. Overall, the obtained results clearly indicate that fish QRFPRs are under positive selection, but the positively selected amino acids did not significantly alter the biochemical properties of these proteins.