The striatum, a major central nervous system structure modulating movement, is enriched with glutamatergic and dopaminergic innervation. By altering activities of both glutamatergic and dopaminergic transmissions the psychostimulants, amphetamine and cocaine, induce behavioral changes in experimental animals. Activation of the two systems is also essential in the mediation of drug-stimulated gene expression in striatal neurons, which is considered to be an important component of the neuroplasticity underlying long-term profiles of stimulant use. Interactions between the two systems occur at multiple levels that determine the final outcome of drug stimulation. Emerging studies on the detailed transsynaptic and intracellular mechanisms of glutamatedopamine interactions in response to stimulant exposure are providing cellular and molecular insight into the pathophysiology of stimulant abuse.