Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) are hypothalamic neuropeptides discovered fourteen years ago. Orexin producing neurons are localized exclusively in the lateral hypothalamus, the classical feeding center. A series of studies suggested that orexin-deficiency causes narcolepsy in humans and other mammalian species, highlighting roles of this hypothalamic neuropeptide in the regulation of sleep and wakefulness. Studies of efferent and afferent systems of orexin-producing neurons have shown that the orexin neuronal system has close interactions with systems that regulate emotion, energy homeostasis, reward, and arousal. Orexin neurons receive abundant input from the limbic system, which might be important for increasing arousal during emotional stimuli. We found that orexin neurons are regulated by sleep active neurons in the ventrolateral preoptic area. Orexin neurons are also regulated by peripheral metabolic cues, including ghrelin, leptin and glucose, suggesting that orexin neurons might provide a link between energy homeostasis and vigilance states. This linkage was shown to play an important role in eliciting behavioral response during fasting. Orexin neurons project to numerous brain regions, with especially strong innervation to the monoaminergic/cholinergic nuclei, in which both subtypes of orexin receptors are localized. These observations suggest that orexin neurons are involved in sensing the body's external and internal environments, and regulate vigilance states accordingly.