JC virus (JCV) is an ubiquitous human polyomavirus which causes persistent infections. The biological cycle of JCV in its host is incompletely known. Most infected individuals remain asymptomatic lifelong despite occasional viral urinary shedding. In some cases of immune depression, JCV may reactivate, gain access to the central nervous system, infect and harm glial cells involved in myelin production, leading to a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML). PML cases have recently increased in patients receiving monoclonal antibody therapies - in particular multiple sclerosis patients treated with natalizumab - raising a new interest in the pathophysiology of JCV infection. The tropism of JCV for glial cells has been associated with various mutations and rearrangements in the non-coding control region (NCCR) of JCV genome, a regulator of viral expression. Several hypotheses have taken into account this hypervariability to explain the pathogenesis of JCV infection.