Nothing is more disappointing for patients than when a promising new treatment hits a roadblock because of unexpected side effects. This is what happened when natalizumab (Tysabri) was associated with a few cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis and Crohn's disease patients, caused by the reactivation of the polyomavirus JC. These dramatic events drew PML squarely into the spotlight and generated considerable interest from the medical community, the pharmaceutical industry, financial markets, and regulatory agencies alike. This scrutiny, in turn, helped crystallize areas of consensus and expose gaps in our understanding of PML pathogenesis. Indeed, since its initial description, there has been a considerable evolution in both the epidemiology and clinical presentations of this disease, and new manifestations of central nervous system infection by polyomavirus JC have been characterized. To keep pace with this opportunistic pathogen, we are therefore forced to reexamine the foundations of our knowledge of virus–host interactions, reappraise our investigational approaches, and in short, rethink PML down to its very name. Hopefully, this crisis will be instrumental in helping us define novel avenues of research, develop predictive tests for PML in populations at risk, and challenge us to find a treatment for this deadly disease. Ann Neurol 2006; 60: 162–173