Multiple arousal systems maintain waking through the actions of chemical neurotransmitters that are released from broadly distributed nerve terminals when the neurons fire. Among these, noradrenaline-, histamine- and orexin-containing neurons fire during waking with behavioral arousal, decrease firing during slow-wave sleep (SWS) and cease firing during paradoxical sleep (PS), which is also known as rapid-eye-movement sleep. By contrast, acetylcholine (ACh)-containing neurons discharge during waking, decrease firing during SWS and fire at high rates during PS in association with fast cortical activity. Neurons that do not contain ACh, including GABA-containing neurons in the basal forebrain and preoptic area, are active in a reciprocal manner to the neurons of the arousal systems: one group discharges with slow cortical activity during SWS, and another discharges with behavioral quiescence and loss of postural muscle tone during SWS and PS. The reciprocal activities and interactions of these wake-active and sleep-active cell groups determine the alternation between waking and sleeping. Selective enhancement and attenuation of their discharge, transmitter release and postsynaptic actions comprise the substrates for the major stimulant and hypnotic drugs.