Progressive multifocal leukoencephalopathy (PML) has been associated with the use of a number of multiple sclerosis (MS) immunomodulatory therapies and has assumed a critical place in the evaluation of their benefit/risk. In this review, we discuss the European Union regulatory approach to drug-induced PML in MS, highlight a number of key issues related to the current knowledge on PML, and outline possible paths to help progress the risk management of patients with MS at risk of PML.