Atypical antipsychotics now represent the mainstay of treatment for patients with schizophrenia. Unfortunately, as a class they have also been associated with an increased risk of weight gain and metabolic abnormalities, including type 2 diabetes. We have investigated the diabetogenic effects of a spectrum of antipsychotics, both atypical and typical. Healthy animals were treated acutely with clozapine (10 mg/kg), olanzapine (3.0 mg/kg), risperidone (1 mg/kg), ziprasidone (3 mg/kg) or haloperidol (0.25 mg/kg) and tested using the hyperinsulinemic-euglycemic and hyperglycemic clamp procedures. Clozapine and olanzapine had a rapid and potent effect on insulin sensitivity by lowering the glucose infusion rate and increasing hepatic glucose production. Both clozapine and olanzapine, as well as risperidone, decreased peripheral glucose utilization. Neither ziprasidone nor haloperidol had a significant impact on insulin sensitivity. In the hyperglycemic clamp, clozapine and olanzapine impaired beta cell function as reflected by a decrease in insulin secretion. Results confirm that 1) antipsychotic medications have an immediate impact on metabolic parameters and 2) the various atypical antipsychotics differ in their propensity to acutely induce metabolic side effects. Our data also support the preclinical use of these clamp procedures in screening putative antipsychotics.