Progressive multifocal leukoencephalopathy (PML) is caused by JC virus (JCV) infection of the central nervous system. PML and other JC virus-associated neurological disorders usually occur in the setting of systemic immunodeficiency caused by other infections (e.g., HIV/AIDS), cancer and immunosuppressive therapies. Several multiple sclerosis-associated DMTs are implicated in the development of PML. PML clinical outcomes depend on both the underlying susceptibility as well as the extent and anatomic location of PML lesions. Monitoring the risk for PML is an evolving area that includes JCV serology and PCR detection as well as neuroimaging. Essential diagnostic tools for PML include neuroimaging and CSF JC virus detection although brain biopsy remains in use. Neurological immune reconstitution inflammatory syndrome (NeuroIRIS) can complicate immune restoration during PML. Therapy for PML is limited although targeting immune checkpoint inhibitors is a promising approach.