Infection by Polyomavirus JC is a model of chronic active viral infection, closely controlled by the immune system. Progressive multifocal leucoencephalopathy (PML) is a deadly demyelinating disease of the central nervous system, consecutive to the lytic infection of oligodendrocytes by JC virus. Reactivation of JC virus occurs only in the setting of severe cellular immune deficiency. During the last 25 years, the incidence of PML has significantly increased related to the AIDS pandemic and, more recently, to the growing use of immunosuppressive drugs. There is no specific antiviral treatment for PML. Nevertheless, the availability of highly active antiretroviral therapy has changed the clinical course of PML in HIV-infected individuals. One-year mortality has decreased from 90 percent to approximately 50 percent as a result of reconstitution of the immune system. Recent advances in JC virus biology give new perspectives to the pathogenesis of PML. New trends in the understanding of the cellular immune response against the JC virus have direct implications for patient management and may lead to develop future strategy of immunotherapies for PML.