Chemokine receptors have been implicated in a wide range of CNS inflammatory diseases and have important roles in the recruitment and positioning of immune cells within tissues. Among them, the chemokine (C-C motif) receptor 5 (CCR5) can be targeted by maraviroc, a readily available and well-tolerated drug that was developed for the treatment of HIV. Correlative evidence implicates the CCR5-chemokine axis in multiple sclerosis, Rasmussen encephalitis, progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome, and infectious diseases, such as cerebral malaria and HIV-associated neurocognitive disorders. On the basis of this evidence, we postulate in this Review that CCR5 antagonists, such as maraviroc, offer neuroprotective benefits in settings in which CCR5 promotes deleterious neuroinflammation, particularly in diseases in which CD8(+) T cells seem to play a pivotal role.