Progressive multifocal leukoencephalopathy (PML) is a severe, often fatal, opportunistic viral infection of the central nervous system that is mainly seen in the context of AIDS and certain monoclonal immune-suppressive therapies. The causative agent, a polyoma virus, named JC virus infects only humans and there is no animal model for PML. This update focuses on information gathered in recent years on the pathogenesis of the disorder, on several clinical aspects associated with diagnosis and therapy, and on the immune reconstitution inflammatory syndrome (IRIS), a complication associated with removal of immunosuppressive therapy in PML.