Progressive multifocal leukoencephalopathy (PML) was a rare disease until the advent of the HIV/AIDS pandemic. Recent interest in the disorder has been spurred by its appearance in patients treated with the monoclonal antibodies natalizumab and rituximab. Unless the accompanying underlying immune deficit can be reversed, PML typically progresses to death fairly rapidly. Treatment directed against the JC virus has been unhelpful, but an increased understanding of disease pathogenesis may result in effective therapeutic strategies.