Progressive multifocal leukoencephalopathy (PML) is a severe and life-threatening central nervous system (CNS) infection caused by the JC virus (JCV), a polyomavirus that typically establishes persistent but asymptomatic infections in a large portion of the general population. The advent of novel immunotherapeutic strategies with the potential to mitigate PML necessitates a thorough reassessment of its pathophysiology and clinical management. PML arises when JCV reactivates in individuals with compromised cellular immunity. Currently, there are no effective antiviral therapies for PML, making the reversal of immunosuppression the cornerstone of treatment and survival. While antiretroviral therapies have substantially decreased the incidence of HIV-associated PML, contemporary immunosuppressive treatments used for cancer, organ transplantation, and chronic inflammatory diseases often create conditions conducive to JCV reactivation. Among these, some specific therapy for multiple sclerosis (mostly natalizumab), have been notable drivers of iatrogenic PML cases. The clinical manifestations of JCV-related diseases have broadened, challenging existing diagnostic criteria and necessitating updates to clinical protocols. Emerging immunotherapeutic interventions, such as checkpoint inhibitors and adoptive T cell transfer, have demonstrated promise in managing PML. However, these approaches require careful oversight to avoid immune reconstitution inflammatory syndrome (IRIS), a potentially fatal hyperimmune response. Even among those who survive PML, significant neurological impairments are common, although without replication of the virus within the CNS. As survival rates increase, this incomplete viral clearance presents new challenges, particularly in the management of the underlying conditions that necessitated immunosuppression. This evolving landscape underscores the need for continued research and innovation in both the treatment of PML and the long-term care of its survivors.