There are two human polyomaviruses, JC virus (JCV) and BK virus (BKV). Most of the population is infected with these viruses at an early age and the viruses can persist indefinitely without known adverse effects in immunocompetent individuals. There are conflicting reports whether these two viruses are latent in the central nervous system or are restricted initially to the renal system. Both JCV and BKV, together with the simian polyomavirus simian virus 40 (SV40), have been associated with central nervous system disease. In particular, JCV is associated with the demyelinating disease progressive multifocal leukoencephalopathy (PML) which was once considered only a rare complication of immunosuppression in transplant recipients. With the advent of the AIDS pandemic, PML has become of increasing importance and is now considered responsible for the death of 4% of HIV-infected individuals. Both BKV and SV40 have been detected in the human central nervous system, but there is still controversy on what correlation, if any, these two viruses have with disease. Current research has focused on the epidemiology and pathogenesis of polyomavirus infections to try to understand the re-activation process in immunosuppressed individuals. This will lead to improvements in the differential diagnosis and treatment of PML. Further analysis of other neurological complications, to see what role polyomavirus plays in these infections, are required.