Recent studies have established that the orexin system is a critical regulator of sleep/wake states. Deficiency of orexin signaling results in the sleep disorder narcolepsy-cataplexy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy-cataplexy. Furthermore, accumulating evidence has indicated that the orexin system regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion, reward, and energy homeostasis. This review presents and discusses the current understanding of the integrative physiology of the orexin system.