Cancer is a multi-step disease involving a series of genetic alterations that result in the loss of control of cell proliferation and differentiation. Such genetic alterations could emerge from the activation of oncogenes and the loss or malfunctioning of tumor suppressor gene activity. Our understanding of cancer has greatly increased through the use of DNA tumor viruses and their transforming proteins as a biological tool to decipher a cascade of events that lead to deregulation of cell proliferation and subsequent tumor formation. For the past ten years our laboratory has focused on the molecular biology of the human neurotropic papovavirus, JCV. This virus causes progressive multifocal Ieukoencephalopathy, a fatal neuro­degenerative disease of the central nervous system in immunocompromised patients. JCV is a common human virus that infects more than 80% of humans but does not induce any obvious clinical symptoms. The increased incidence of acquired immune deficiency syndrome and the use of immunosuppressive chemotherapy have dramatically raised the incidence of PML. The coincidental occurrence of malignant astrocytes and oligodendrocytes in PML patients, coupled with the induction of glioblastoma in JCV-intected non­human primates, provides intriguing speculation on the association between JCV and CNS malignancies. In this report we discuss clinical data and laboratory observations pointing to the direct involvement of JCV in cancer.