The finding that activation of peroxisome proliferator-activated receptor-γ (PPARγ) suppresses inflammation in peripheral macrophages and in models of human autoimmune disease instigated the evaluation of this salutary action for the treatment of CNS disorders with an inflammatory component. The fact that NSAIDs delay the onset of and reduce the risk of developing Alzheimer's disease (AD), while also binding to and activating PPARγ, led to the hypothesis that one dimension of NSAID protection in AD is mediated by PPARγ. Several lines of evidence from experiments using AD-related transgenic cellular and animal models have supported this hypothesis. The capacity of PPARγ agonists to elicit anti-inflammatory, anti-amyloidogenic and insulin-sensitizing effects might account for their observed protective effects. Several clinical trials employing PPARγ agonists have yielded promising results, and further trials are in preparation. Positive outcomes following PPARγ administration have been obtained in animal models of other neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, both of which are associated with a considerable degree of neuroinflammation. Finally, activation of PPARγ has been found to be protective in several models of multiple sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARγ activation in patients with multiple sclerosis.