Many antipsychotic drugs disturb the regulation of glucose metabolism in patients treated for schizophrenia. The goal of the present studies was to determine if these antipsychotic drugs produce hyperglycemia in mice in relation to their ability to interfere with glucose uptake and utilization. Male C57BL/6 mice were injected with a panel of typical and atypical antipsychotic drugs and blood glucose levels were determined periodically over a 3- to 6-h time interval. The atypical drugs, clozapine, desmethylclozapine, quetiapine, and loxapine, and the original antipsychotic, chlorpromazine, induced significant hyperglycemia in the mice in accordance with their effects on glucose transport. By contrast, haloperidol and sulpiride, which have little effect on glucose uptake, did not induce hyperglycemia. Risperidone produced a modest elevation of blood glucose levels, but only at a low dose of the drug. Cytochalasin B, a specific inhibitor of the glucose transporter (GLUT) protein, produced significant hyperglycemia in the mice. Overall, there was a strong correlation between the ability of a drug to inhibit glucose transport in vitro and its ability to induce hyperglycemia in vivo. Finally, the drugs that produced hyperglycemia in mice have been linked to the development of diabetes in patients.