Protective immune responses in the central nervous system (CNS) must act efficiently but need to be tightly controlled to avoid excessive damage to this vital organ. Under homeostatic conditions, the immune surveillance of the CNS is mediated by innate immune cells together with subsets of memory lymphocytes accumulating over lifetime. Accordingly, a wide range of immune responses can be triggered upon pathogen infection that can be associated with devastating clinical outcomes, and which most frequently are due to neurotropic viruses. Here, we discuss recent advances about our understanding of anti-viral immune responses with special emphasis on mechanisms operating in the various anatomical compartments of the CNS.