Antipsychotic drugs used in the treatment of schizophrenia have in common the property of being dopamine-receptor antagonists. However, the rapid timecourse of receptor blockade produced upon drug administration does not correlate with the emergence of clinical actions, which typically require weeks of treatment to become manifest. Studies in rats have shown that repeated antipsychotic drug treatment results in a delayed inactivation of dopamine-neuron firing in the midbrain due to depolarization block. Furthermore, the therapeutic efficacy of antipsychotic drugs in humans correlates with their ability to induce depolarization block of mesolimbic dopamine neurons, whereas their potential to produce extrapyramidal side effects correlates with their propensity for inducing depolarization block in the nigrostriatal dopamine system. Therefore, dopamine-cell depolarization block is an effective model for evaluating antipsychotic drug efficacy, and provides a potential mechanism to account for their therapeutic impact on a dysregulated dopamine system.