Using positional cloning in a canine model of narcolepsy and mouse gene knockouts, genes involved in the pathogenesis of narcolepsy in animals have been identified. Hypocretin/orexin ligand and hypocretin/orexin receptor genes are key to the pathogenesis of narcolepsy in animals. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in many cases. Hypocretins/orexins are novel hypothalamic neuropeptides involved in various hypothalamic mechanisms, such as energy homeostasis and neuroendocrine function. Hypocretin-deficient human narcolepsy appears to be a more complex condition than a simple sleep disorder, and it may serve as an important disease model for studying hypothalamic function in health and disease.