Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the human central nervous system. It destroys oligodendrocytes leading to neurological deficits associated with demyelination. It most commonly occurs in HIV-infected patients, but increasing numbers of patients are being recognized in the context of immunosuppressive therapies for autoimmune diseases. The precise pathogenesis of infection by JC virus, a human papovavirus remains elusive, but much has been learned since the original description of the pathologic entity PML in 1958. Detection and diagnosis of this disorder has become more sophisticated with MR imaging of the brain and spinal fluid analysis using polymerase chain reaction (PCR) techniques. Immune reconstitution inflammatory syndrome complicates reversal of immunosuppression when PML has established a foothold in the brain. No effective therapy exists, but there is hope for both better management of patients diagnosed with exogenous immunosuppression and future prospects for antiviral therapy.