Progressive multifocal leucoencephalopathy (PML) is a rare and often fatal opportunistic infection that has been well reported in patients with rheumatic diseases. The contributions of predisposing factors such as underlying disease and immunosuppressive drug selection are incompletely understood but it would appear that patients with systemic lupus erythematosus may be at highest risk. Natalizumab, a biological agent approved for multiple sclerosis and Crohn's disease has the clearest pattern of small but definite risk. Although the risk due to rituximab is difficult to assess given the multiple confounders, continued vigilance is warranted. Rheumatologists need to become familiar with PML and feel able to help patients make shared and informed decisions about the risks when starting treatment with immunosuppressive therapies. In particular, rheumatologists need to be vigilant and pursue the diagnosis of PML in all patients with unexplained neurological signs or symptoms with clinical and MRI findings compatible with the diagnosis.