Polyglutamine diseases are a class of inherited neurodegenerative disorders caused by the expansion of a polyglutamine tract within the respective proteins. Clinical studies have revealed that the forming of neuronal intranuclear inclusions by the disease protein is a common pathological feature of polyglutamine diseases. Although there has been considerable progress in understanding polyglutamine diseases, many questions regarding their mechanism are still unanswered. The finding that molecular chaperones are associated with ubiquitinated intranuclear inclusions clearly indicates a crucial role of molecular chaperones in the generation of these fatal diseases. Molecular and chemical chaperones have been found to be a good agent for suppressing many polyglutamine diseases in several animal models. In this review, I discuss the roles of the ubiquitin-proteasome pathway and molecular chaperones in the development of polyglutamine diseases and probable approach for the prevention of many of these fatal disorders using molecular chaperones as a therapeutic agent. Newly found chemical chaperones have been demonstrated to be potentially useful and could be used as a therapeutic strategy in preventing many versions of polyglutamine diseases.