The vertebrate Neuropeptide S (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 NPSR–NPS system is closely related to the vasopressin-like receptor–vasopressin/oxytocin peptide (VPR–VP/OT) system. Single nucleotide polymorphisms (SNPs) and isoforms in the human NPSR gene are associated with risks of asthma, bronchial hyper-responsiveness, immunological disorders such as rhinoconjunctivitis, respiratory distress syndrome and irritable bowel syndrome. Consequently, potent NPSR antagonists have potential for multiple clinical applications for the treatment of obesity, hypersomia and anxiety disorders[1].