Recent studies have implicated the orexin system as a critical regulator of sleep/wake states, feeding behavior, and reward processes. Orexin deficiency results in narcolepsy-cataplexy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. Orexin agonists and antagonists are thought to be promising avenues toward the treatment of sleep disorders, eating disorders, and drug addiction. In this chapter, we discuss the current understanding of the physiological roles of orexins in regulation of arousal, sleep/wake states, energy homeostasis, and reward systems.