The orexin (hypocretin) neuropeptide system is comprised of two peptides (orexin A and B) exclusively synthesised in the lateral hypothalamus, and two GPCRs (orexin 1 and 2 receptors, Ox1R and Ox2R) which are widely distributed across the brain. Orexins are centrally involved with the stabilisation wakefulness, since orexin producing cells are active during wake and inactive during sleep, whereas very low/absent levels of orexin producing cells causes narcolepsy with cataplexy. This rare disorder is characterised by excessive daytime sleepiness, disrupted nighttime sleep and rapid shifts from wakefulness to REM sleep-like states and the sudden loss of muscle tone (cataplexy). In one of the most rapid transitions from discovery to pharmaceutical development, the first clinical study with a dual orexin receptor antagonist (DORA), almorexant, demonstrated the hypnotic effects of this class of compounds only 9 years after the discovery of the orexin system. Three DORAs are now registered for the treatment of insomnia (suvorexant, lemborexant and daridorexant), whereas Ox2R-selective antagonists are also in development as hypnotics (e.g. seltorexant). These compounds differ markedly from classical hypnotics by facilitating REM sleep. This unprecedented control over sleep architecture lends itself as a potential therapeutic strategy for a range of disorders from PTSD to Alzheimer’s and Parkinson’s disease. Data on these from our laboratory will be shown in this talk. Ox2R agonists also are in development for the stabilisation of wakefulness for, e.g. in narcolepsy with cataplexy. Furthermore, the wide distribution of orexin receptors across the brain subscribes a wealth of other physiological functions, as exemplified by our recent work on the role of Ox1Rs in decision-making. This talk will describe the development of orexinergic agents and highlight the potential of this system as a therapeutic target for a series of neurologic and neuropsychiatric disorders.