Multiple neuronal systems contribute to the promotion and maintenance of the wake state, which is characterized by cortical activation and behavioral arousal. Using predominantly glutamate as a neurotransmitter, neurons within the reticular formation of the brainstem give rise to either ascending projections into the forebrain or descending projections into the spinal cord to promote through relays fast cortical activity or motor activity with postural muscle tone. Using acetylcholine, cholinergic neurons in the brainstem project to forebrain relays and others in the basal forebrain to the cortex, by which they stimulate fast gamma activity during waking and during rapid eye movement or paradoxical sleep (PS). Other neuromodulatory systems, such as noradrenergic locus coeruleus neurons, give rise to highly diffuse projections through brain and spinal cord and simultaneously stimulate cortical activation and behavioral arousal. Although such neuromodulatory systems were thought to be redundant, a recently discovered peptide called orexin (Orx) or hypocretin, contained in diffusely projecting neurons of the hypothalamus, was found to be essential for the maintenance of waking with muscle tone, since in its absence narcolepsy with cataplexy occurred. Orx neurons discharge during active waking and cease firing during sleep. Since cholinergic neurons discharge during waking and PS, they would stimulate cortical activation in association with muscle tone when orexinergic neurons are also active but would stimulate cortical activation with muscle atonia when orexinergic neurons are silent, as in natural PS, or absent, as in pathological narcolepsy with cataplexy.