The neuropeptides orexin A and orexin B (also called hypocretin 1 and 2) were recently discovered by a "reverse pharmacology" approach as ligands for two previously orphan G protein coupled receptors: orexin receptors 1 and 2. Neurons producing orexins are located exclusively in the lateral hypothalamic area but project broadly to various parts of the brain, and they have been implicated in the control of energy homeostasis and arousal maintenance. The orexin receptors are also broadly expressed in the central nervous system. Murine and canine models suggest that defective signaling in the orexin system is responsible for the sleep/wake disorder narcolepsy. Although narcoleptic patients rarely have genetic defects in the orexin system, they lack these neuropeptides in the brain and cerebrospinal fluid, indicating that human narcolepsy is an orexin deficiency syndrome in the majority of cases. A connection between sleep/wake regulation and energy homeostasis is hypothesized with orexin neuropeptides as a molecular link.