The involvement of dopamine (DA) in drug reinforcement is well established, but much less in known about its contribution to addiction. We have used positron emission tomography to investigate in humans the role of DA in drug reinforcement, addiction and drug vulnerability. We have shown that during drug intoxication increases in striatal DA are associated with the drug's reinforcing effects only if the DA changes occur rapidly. These results corroborate the relevance of drug-induced DA increases and of pharmacokinetics in the rewarding effects of drugs in humans. During withdrawal, we have shown significant reductions in DA D(2) receptors and in DA release in drug abusers, which is likely to result in decreased sensitivity to non-drug-related reinforcing stimuli. The DA D(2) reductions were associated with decreased activity in the orbitofrontal cortex, which we postulate is one of the mechanisms underlying compulsive drug administration in the addict. In fact, during craving the orbitofrontal cortex becomes hyperactive in proportion to the desire for the drug. In non-drug-abusing subjects striatal DA D(2) receptors levels predicted the reinforcing responses to stimulant drugs, providing evidence that striatal DA D(2) receptors modulate reinforcing responses to stimulants in humans and may contribute to the predisposition for drug self-administration.