Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the white matter of the human brain caused by lytic infection of oligodendrocytes with the human polyomavirus JCV. Although the majority of PML cases occur in severely immune-suppressed individuals, with HIV-1 infection as the predominant factor, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies that modulate immune system functions. Monoclonal antibodies that target the cell adhesion molecules VLA-4 (natalizumab; Tysabri for multiple sclerosis and Crohn's disease) or LFA-1 (efalizumab; Raptiva for severe forms of plaque psoriasis) to prevent extravasation of inflammatory T cells into tissues, or target the cell surface marker CD20 (rituximab; Rituxan for hematologic malignancies and rheumatoid arthritis) to deplete peripheral circulating B cells, have all been associated with PML. The link between the effects of these therapies on the immune system and the occurrence of PML has prompted investigations on JCV sites of latency in the bone marrow, the migration of bone marrow derived cells into the circulation, and intracellular virus entry into the brain.