Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics.