Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease that affects immunocompromised hosts. Most often the disease is reported in association with leukemia, lymphoma, and AIDS. With recent advancements in immunosuppressive medications and subsequent rise in solid organ transplantations, it is becoming more prevalent in this population. Both the diagnosis and treatment of PML remains a challenge to the transplant community. The disease remains mostly underreported and undertreated. The diagnostic uncertainty in a renal transplant patient leads us to do the brain biopsy for suspicion and confirmation of PML.