"Atypical" antipsychotics are associated with a much lower propensity for extrapyramidal side effects and, with some exceptions, a lack of sustained prolactin elevation. The authors propose that a low-affinity and fast dissociation (in molecular terms) from the dopamine D(2) receptor, along with administration of the drug in doses that lead to appropriate levels of dopamine D(2) receptor blockade, are the most important requirements for atypicality. Actions at other receptors (5-HT(2), D(4), etc.) may not be necessary to achieve atypicality, and while action at these receptors may have benefits on symptoms such as mood and cognition, this is as yet to be conclusively proven. Why clozapine is effective in refractory patients is still elusive and efforts to make antipsychotics that are devoid of effects on the dopamine D(2) receptors so far have been unsuccessful. In light of this, the authors provide a heuristic model linking pathophysiology and therapeutics and suggest that the ideal treatment for schizophrenia is unlikely to be single-drug with multireceptor blockade (a sort of one-size-fits-all polypharmacy) but will require several specific and targeted treatment strategies that are titrated to match the variable expression of different dimensions of schizophrenia in each patient.