JC virus, a human neurotropic polyomavirus, is the established etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually affects individuals with defects in cell-mediated immunity. Cytolytic destruction of oligodendrocytes, the myelin-producing cells of the central nervous system is attributed as the mechanism by which JCV induces demyelination. PML was at one time a rare complication however it is now a much more common disease affecting patients of all ages due to the prevalence of AIDS. Of interest, in vitro evidence points to a cooperative interaction between JCV and HIV-1, via the HIV-1 regulatory protein, Tat. In addition, JCV has been demonstrated to induce tumors of neural origin in several animal models, including rodents and non-human primates, and several clinical reports have suggested a possible association between JCV and glial-origin tumors in humans. The viral regulatory protein, T-antigen, which has been shown to play a key role in orchestrating the events of the viral lytic cycle, is also capable of altering cellular functions, by nature of its direct interaction with cellular regulatory proteins and by its effect on cellular transcription. In this review, we discuss clinical aspects of PML, the ability of JCV to induce tumors in animal models, and the ability of JCV T-antigen to alter cellular function in vitro.