The peroxisome proliferator activated receptors (PPARs), which belong to the nuclear receptor superfamily, are key regulators of glucose and fat metabolism. The PPAR-gamma isoform is involved in the regulation of cellular glucose uptake, protection against atherosclerosis and control of immune reactions. In addition, the activation of PPAR-gamma effectively attenuates neurodegenerative and inflammatory processes in the brain. Here, we review a novel aspect of beneficial and clinically relevant PPAR-gamma actions: neuroprotection against ischemic injury mediated by intracerebral PPAR-gamma, which is expressed in neurons and microglia. Together with the recent observation that the PPAR-gamma ligand pioglitazone reduces the incidence of stroke in patients with type 2 diabetes, this review supports the concept that activators of PPAR-gamma are effective drugs against ischemic injury.