The efferent and afferent systems of orexin neurons suggest interactions between these cells and important feeding centers in the hypothalamus, arousal and sleep-wakefulness centers in the brainstem, sympathetic and parasympathetic nuclei, and the limbic system. Numerous studies have documented that acute intracerebroventricular administration of orexin dose-dependently increases arousal-associated behavioral and physiological processes including food intake, waking time, motor activity, and metabolic rate, as well as heart rate and blood pressure in many species. Furthermore, it is likely that orexin-mediated food intake results partly from stimulation of feeding pathways in the hypothalamus such as those involving the NPY pathway. Recent electrophysiological studies have shown that orexin neurons are regulated by metabolic cues, including leptin, glucose, and ghrelin. Thus, orexin neurons have the requisite anatomical connections and interactions with hypothalamic feeding pathways, and regulation by circadian and nutritional factors to suggest that they may be an important cellular and molecular link in the integration of sleep and energy homeostasis.