Currently accepted treatments for schizophrenia can effectively control positive symptoms but have limited impact on cognitive deficits in schizophrenia. The purpose of these experiments was to address this unmet need by characterizing the effects of classical and second-generation antipsychotics on cognitive impairments associated with schizophrenia. An additional aim was to characterize the part(s) of the pharmacological profile of drugs that were important to reverse deficits. Cognitive deficits were assessed using a frontally mediated attentional set-shifting task in rats that is analogous to tasks used in humans and nonhuman primates that assess executive function. Mirroring findings in patients with schizophrenia, the classical antipsychotic haloperidol was ineffective in treating set-shifting deficits induced by subchronic treatment with phencyclidine (PCP). Similarly, second-generation antipsychotics, risperidone, clozapine, and olanzapine were ineffective. In contrast, selected doses of sertindole and the 5-HT(6) receptor antagonist SB 271046 attenuated PCP-induced set-shifting deficits. Finally, the 5-HT(2A) receptor antagonist M100907 was without effect. Further examination revealed that repeated treatment (21 days) with sertindole, but not olanzapine, also was effective in reversing the executive function deficit. These data suggest that the combination of 5-HT(6) antagonistic activity and the absence of antimuscarinic activity may represent key characteristics of the pharmacological profile for improved antipsychotic drugs for schizophrenia.