Hypocretins (also called orexins) are two newly discovered neuropeptides originating from the same precursor, preprohypocretin. The amino-acid sequences of hypocretin are highly conserved among vertebrates. Cells bodies of hypocretin neurons are restricted mainly to the lateral and ventral hypothalamus, while hypocretin fibers project throughout the brain, including several areas implicated in the regulation of the sleep/wakefulness cycle. Hypocretins act on their targets via two specific, membrane-bound, G-protein-coupled receptors, Hcrtr-1 and Hcrtr-2. Among the various physiological actions ascribed to hypocretins, the strongest evidence are for their involvement in the integration and stabilization of arousal networks. Degeneration of hypocretin neurons or genetic mutations that prevent the normal synthesis of hypocretins, or their receptors, cause human and animal narcolepsy, a neurological disorder of excessive sleepiness and abnormalities in REM sleep. Recent data point to an autoimmune origin for human narcolepsy. It is believed that understanding the role of hypocretins in the pathology of narcolepsy will create the basis for the development of new strategies to effectively treat this disease.