Since all antipsychotics block dopamine D₂ receptors, the authors investigated how well D₂ receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2.5 mg/day of haloperidol. After 2 weeks of treatment, D₂ receptor occupancy was determined with [¹¹C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. The patients showed a wide range of D₂ occupancy (38%–87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D₂ occupancy exceeded 65%, 72%, and 78%, respectively. The study confirms that D₂ occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a “target and trigger” hypothesis of antipsychotic action, i.e., that the D₂ receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D₂ occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.