Narcolepsy is a disabling neurologic condition affecting 1 in 2000 individuals, characterized by sleepiness, cataplexy, and transitions from wakefulness into rapid-eye-movement sleep. Current treatments include amphetamine-like stimulants and antidepressants. Human narcolepsy is HLA-associated, multigenic, and environmentally influenced. Positional cloning was used to isolate narcolepsy genes in canine families with autosomal recessive narcolepsy transmission. Three mutations in the G-protein-coupled hypocretin (orexin) receptor-2 (Hcrtr-2) gene were identified. In humans, most cases of narcolepsy are not linked to hypocretin (Hcrt) ligand or receptor mutations but are associated with undetectable cerebrospinal fluid Hcrt-1 levels. A single Hcrt gene/narcolepsy mutation was identified in narcoleptic patients. Hcrt-1 is wake-promoting in vivo, and studies in sporadic human narcolepsy indicate a loss of brain Hcrt-1 and Hcrt-2 and a disappearance of Hcrt-1-containing cells in the hypothalamus. Narcolepsy with cataplexy may therefore be due to Hcrt deficiency. The HLA association in humans suggests possible autoimmune activity against hypothalamic Hcrt-containing cells. Hypocretins may also have roles in regulating normal sleep, appetite, neuroendocrine function and energy metabolism, uniquely positioning them as a link between multiple important behaviors. Abnormal Hcrt transmission is also found in neurologic disorders featuring excessive daytime sleepiness and/or hypothalamic abnormalities. Pharmacologic manipulations of Hcrts may have multiple therapeutic applications.