The neuropeptide S receptor (NPSR) belongs to the G protein-coupled receptor (GPCR) superfamily and is activated by the neuropeptide S (NPS). Although recently discovered, the vertebrate NPSR-NPS system has been established as an important signaling system in the central nervous system and is involved in physiological processes such as locomotor activity, wakefulness, asthma pathogenesis, anxiety and food intake. The availability of a large number of genome sequences from multiple bilaterian lineages has provided an opportunity to establish the evolutionary history of the system. This review describes the origin and the molecular evolution of the NPSR-NPS system using data derived primarily from comparative genomic analyses. These analyses indicate that the NPSR-NPS system and the vasopressin-like receptor-vasopressin/oxytocin peptide (VPR-VP/OT) system originated from a single system in an ancestral bilaterian. Multiple duplications of this ancestral system gave rise to the bilaterian VPR-VP/OT system and to the protostomian cardioacceleratory peptide receptor-cardioacceleratory peptide (CCAPR-CCAP) system and to the NPSR-NPS system in the deuterostomes. Gene structure features of the receptors were consistent with the orthology annotations derived from phylogenetic analyses. The orthology of the peptide precursors closely paralleled that of the receptors suggesting an ancient coevolution of the receptor-peptide pair. An important challenge for the coevolution hypothesis will be to establish the molecular and structural basis of the divergence between orthologous receptor-ligand pairs in this system. © 2014 Elsevier Inc.