The first step in the management of progressive multifocal leukoencephalopathy (PML) is awareness of the disease. Patients vulnerable to PML are those with immunosuppression, either through their disease or use of immune-modulating therapy. In patients susceptible to PML who exhibit focal neurologic signs and symptoms, brain magnetic resonance imaging can detect the telltale PML brain lesions--subcortical white matter hyperintense areas on T2-weighted images and fluid-attenuated inversion recovery sequences and hypointensity on T1-weighted images, typically without enhancement. Demonstration of JC virus DNA by ultrasensitive polymerase chain reaction in cerebrospinal fluid is diagnostic for PML. Immune restoration whenever possible is the cornerstone of treatment. Highly active antiretroviral therapy has dramatically improved the prognosis for patients infected with human immunodeficiency virus. Alternatively, restoration of immunity is frequently attended by the immune reconstitution inflammatory syndrome which can be clinically devastating or even fatal. In the case of natalizumab-associated PML, withdrawal of therapy and prompt institution of plasmapheresis to desaturate target receptors provides the best chance for long-term survival.