Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by infection of oligodendrocytes by JC virus. As patients with HIV survive longer with severe immunodeficiency, the incidence of PML is rising. Diagnosis is not always easy and the gold standard remains histological confirmation of the characteristic lesions of PML which requires a brain biopsy. This is considered too invasive by many clinicians and patients alike and detection of JC virus DNA in the cerebrospinal fluid (CSF) using polymerase chain reaction (PCR) is used as an alternative to biopsy. JC virus subtype detection in brain, CSF and blood leukocytes may offer further diagnostic and prognostic possibilities. The aetiology, clinical features and diagnostic problems of PML are reviewed. At present the outlook for patients with confirmed PML is poor and there is currently no effective treatment. However, novel approaches to treatment are under investigation and show some promise.