Many neurochemically distinct systems interact to regulate wakefulness and sleep. Wakefulness is promoted by brainstem and hypothalamic neurons producing acetylcholine, norepinephrine, dopamine, serotonin, histamine, and orexin/hypocretin. Each of these arousal systems is capable of increasing wakefulness, but coordinated activity in all these pathways is required for complete alertness and cortical activation. Neurons in the pons and preoptic area control rapid eye movement and non-rapid eye movement sleep. Mutual inhibition between these wake- and sleep-regulating regions likely helps generate discrete behavioral states. An up-to-date understanding of these systems should allow clinicians and researchers to better understand the effects of drugs, lesions, and neurologic disease on sleep and wakefulness.