In the era of the AIDS pandemic, progressive multifocal leukoencephalopathy (PML) has ceased being a rare disease. Prevalence estimates from clinical and pathological series suggest that up to 5% of all HIV-infected persons will develop PML. The extraordinary frequency with which PML attends HIV infection vastly exceeds its appearance in association with other predisposing conditions and has resulted in it no longer being considered a rare disorder. Why PML appears to be far more common with AIDS than with other underlying immunosuppressive conditions remains unexplained. Potential explanations include an alteration of the CNS milieu by HIV facilitating JC viral entry into the brain and activation of the JCV by HIV proteins, e.g., tat, and by inflammatory byproducts of HIV infection. It is quite likely that multiple diverse mechanisms are at play.