Progressive multifocal leukoencephalopathy is a viral-induced demyelinating disease of the central nervous system usually occurring in the immunocompromised individual. The incidence of progressive multifocal leukoencephalopathy has risen sharply over the past decade because of widespread human immunodeficiency virus infection leading to immunodeficiency. This increased incidence of progressive multifocal leukoencephalopathy may also be due to better recognition of its clinical signs, and more rapid and reliable laboratory diagnosis of JC virus, the etiologic agent. There have also been advances in the molecular detection of the JC virus and the identification of variations in the viral genome sequence that may affect its multiplication cycle in different tissues. Clinical and basic research have resulted in a better understanding of the pathogenesis of progressive multifocal leukoencephalopathy and have provided sufficient information to plan new approaches for treatment.