This cutting-edge review of the orexin/hypocretin system sets the stage for advanced research on the pathological mechanisms underlying the loss of orexin/hypocretin neurons in humans, regulation of sleep and wakefulness by the orexin/hypocretin system, and the role of the orexin/hypocretin system in many other physiological processes, including feeding, autonomic regulation, and neuroendocrine regulation. Topics of interest include assessment of functions and the physiology of orexin/hypocretin, its pathophysiology in human narcolepsy-cataplexy, and possible treatments and pharmacology. The authors also introduce several experimental methods for orexin/hypocretin research, and, using multidisciplinary approaches, explain their uses and limitations.