In T-cell-mediated autoimmune diseases of the central nervous system (CNS), CD4 T cells have long been regarded as the only pathogenetically relevant T-cell population. However, growing clinical and experimental evidence suggests that CD8 T cells also contribute significantly to autoimmune responses in the CNS. We discuss the potential induction of autoimmune CD8 T cells by infections, the impact of the microenvironment of the CNS on CD8 T-cell responses, and the potential interaction of CD8 T cells with autoantigen-expressing resident brain-cell populationsneurons in particularin light of clinical and experimental findings.