Repeated intermittent treatment with psychomotor stimulants or opiates sensitizes animals to the locomotor activating effects of these drugs. Whereas such sensitization may have important implications for the understanding of addiction, mental illness, and the cellular basis of memory, its mechanisms remain only partially understood. Psychomotor-stimulant sensitization can result in relatively permanent changes in the response of the mesolimbic dopamine system to these agents and to a variety of stressors, but the process does not depend upon simple activation of dopaminergic neurons. Psychomotor sensitization can be produced by direct (apomorphine, bromocriptine) and indirect (amphetamine, cocaine) dopamine agonists that inhibit the firing of dopaminergic neurons and thus reduce impulse-dependent dopamine release. Moreover, some treatments that cause dopaminergic activation and dopamine (DA)-dependent locomotion fail to cause robust psychomotor sensitization. While nucleus accumbens injections of amphetamine cause DA release and enhanced locomotion, they do not sensitize the animals to subsequent systemic amphetamine. On the other hand, ventral tegmental injections of amphetamine inhibit the DA system and DA-dependent locomotion but none the less sensitize the animal to subsequent systemic amphetamine treatment. While some drugs (cocaine, amphetamine, morphine, heroin) cross-sensitize animals to each other, other drugs (bromocriptine, quinpirole) sensitize animals to themselves and each other but not to cocaine or heroin. While some cases of sensitization involve Pavlovian association of environmental cues with the drug state, others seem largely independent of such conditioning. Thus it appears that there is more than one phenomenon and more than one mechanism of psychomotor sensitization.