Although atypical antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic “atypical” is not clear. This article provides a new hypothesis about the mechanism of action of atypical antipsychotics. Published data regarding the molecular, animal model, neuroimaging, and clinical aspects of typical and atypical antipsychotics were reviewed to develop this hypothesis. Particular attention was paid to data regarding the role of the serotonin 5-HT₂ and dopamine D₄ receptors in atypicality. Neuroimaging data show that optimal dopamine D₂ occupancy is sufficient to produce the atypical antipsychotic effect. Freedom from motor side effects results from low D₂ occupancy, not from high 5-HT₂ occupancy. If D₂ occupancy is excessive, atypicality is lost even in the presence of high 5-HT₂ occupancy. Animal data show that a rapid dissociation from the D₂ receptor at a molecular level produces the atypical antipsychotic effect. In vitro data show that the single most powerful predictor of atypicality for the current generation of atypical antipsychotics is fast dissociation from the D₂ receptor, not its high affinity at 5-HT₂, D₄, or another receptor. The authors propose that fast dissociation from the D₂ receptor makes an antipsychotic more accommodating of physiological dopamine transmission, permitting an antipsychotic effect without motor side effects, prolactin elevation, or secondary negative symptoms. In contrast to the multireceptor hypotheses, the authors predict that the atypical antipsychotic effect can be produced by appropriate modulation of the D₂ receptor alone; the blockade of other receptors is neither necessary nor sufficient.