Psychostimulant drugs like amphetamine are readily self-administered by humans and laboratory animals by virtue of their actions on dopamine (DA) neurons in the midbrain. Exposing animals to this drug either systemically or in the cell body region of these neurons in the ventral tegmental area leads to long-lasting alterations in dopaminergic function. These have most often been assessed as increased locomotor activity and enhanced DA overflow in the nucleus accumbens (NAcc) after re-exposure to the drug weeks to months later. Evidence is presented showing that manipulations that produce this sensitization of midbrain DA neuron reactivity enhance the pursuit and self-administration of psychostimulant drugs. Procedures known to prevent the induction of sensitization by amphetamine also prevent the facilitation of drug taking. Enhanced drug self-administration and primed reinstatement of drug seeking are also accompanied by enhanced NAcc DA reactivity. Finally, drugs that increase NAcc DA overflow acutely but fail to produce sensitization of this effect are not associated with the subsequent enhancement of self-administration. These results indicate a direct relationship between the sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and self-administration of psychostimulant drugs. Understanding the neuronal events and adaptations that underlie the induction and expression of sensitization may thus help elucidate how drug abuse develops, how it is reinstated and ultimately how both may be prevented.