Protein misfolding and aggregation in the brain have been implicated as a common molecular pathogenesis of various neurodegenerative diseases including Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis, and the polyglutamine (polyQ) diseases. The polyQ diseases are a group of nine hereditary neurodegenerative diseases, including Huntingtons disease (HD) and various types of spinocerebellar ataxia (SCA), which are caused by abnormal expansions of the polyQ stretch ( > 35-40 repeats) in unrelated disease-causative proteins. The expanded polyQ stretch is thought to trigger misfolding of these proteins, leading to their aggregation and accumulation as inclusion bodies in affected neurons, eventually resulting in neurodegeneration. Misfolding and aggregation of the polyQ protein are the most ideal therapeutic targets since they are the most upstream events in the pathogenic cascade, and therefore, therapeutic approaches using molecular chaperones, which prevent protein misfolding and assist the refolding of misfolded proteins, are being extensively investigated. Indeed, a variety of molecular chaperones such as Hsp70 and Hsp40 have been demonstrated to exert therapeutic effects against various experimental models of the polyQ diseases. Furthermore, toward developing pharmacological therapies, small chemical activators of heat shock transcription factor 1 (HSF1) such as geldanamycin and its derivative 17-AAG, which induce multiple endogenous molecular chaperones, have been proven to be effective not only in polyQ disease models, but also in other neurodegenerative disease models. We hope that brainpermeable molecular chaperone inducers will be developed as drugs against a wide range of neurodegenerative diseases in the near future.