Extensive research has provided substantial insight into the neurobiological mechanisms underlying the reinforcing, locomotor-activating and stereotypy-inducing actions of psychostimulants. The diverse behavioral effects of these drugs are superimposed on potent arousal-enhancing actions. Psychostimulant-induced arousal is a prominent contributing factor to the widespread use and abuse of these drugs. Moreover, enhanced arousal may be a critical component of the reinforcing and other behavioral actions of these drugs. Although long overlooked, recent work begins to identify the neural mechanisms involved in psychostimulant-induced arousal. For example, microdialysis studies demonstrate a close relationship between amphetamine-induced waking/arousal and amphetamine-induced increases in norepinephrine and dopamine efflux. Additionally, it is now clear that both norepinephrine and dopamine exert robust wake-promoting actions. The wake-promoting effects of norepinephrine involve synergistic actions of alpha1- and beta-receptors, whereas dopamine-induced waking involves both D1 and D2 receptors. Finally, additional studies have identified subcortical regions involved in the wake-promoting actions of both norepinephrine and amphetamine. These regions include, but may not be limited to, the medial septal area, the medial preoptic area, and the lateral hypothalamus. Combined, these and other observations indicate a prominent involvement of both norepinephrine and dopamine in stimulant-induced arousal via actions within a network of subcortical regions. Although it is clear that both norepinephrine and dopamine contribute to psychostimulant-induced arousal, the degree to which each transmitter system is necessary for the expression of stimulant-induced arousal remains to be fully elucidated.