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Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system. It has been recently associated with selective immunosuppression in patients with multiple sclerosis. This review describes the pathogenesis, clinical presentation, diagnosis, and treatment of natalizumab-associated PML.Treatment of multiple sclerosis with natalizumab first involves risk stratifying patients. Clinicians can employ new tools for risk stratification including JC-virus antibody status, prior immunosuppression, and length of natalizumab treatment. These tools can help minimize the risk of developing PML. Identifying patients with natalizumab-associated PML poses a diagnostic challenge for clinicians. Unique clinical features, sensitive laboratory analyses, and advanced MRI techniques have been identified that aid in the diagnosis of natalizumab-associated PML.There continues to be significant gaps in our understanding of PML pathogenesis and its relationship with therapeutic immunosuppression. There have been advances made in our ability to treat multiple sclerosis, although these have come with the unintended risk of PML. Fortunately, natalizumab-associated PML remains a rare entity compared to multiple sclerosis-associated disability, and the risk may be mitigated with appropriate patient selection, accurate and rapid diagnosis, and aggressive treatment strategies.