Multiple sclerosis afflicts more than 1 million individuals worldwide and is widely considered to be an autoimmune disease. Traditionally, CD4⁺ T helper cells have almost exclusively been held responsible for its immunopathogenesis, partly because certain MHC class II alleles clearly predispose for developing multiple sclerosis and also, because of their importance in inducing experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. However, several strategies that target CD4⁺ T cells beneficially in EAE have failed to ameliorate disease activity in multiple sclerosis, and some have even triggered exacerbations. Recently, the potential importance of CD8⁺ T cells has begun to emerge. Physiologically, CD8⁺ T cells are essential for detecting and eliminating abnormal cells, whether infected or neoplastic. In multiple sclerosis, genetic associations with MHC class I alleles have now been established, and CD8⁺ as well as CD4⁺ T cells have been found to invade and clonally expand in inflammatory central nervous system plaques. Recent animal models induced by CD8⁺ T cells show interesting similarities to multiple sclerosis, in particular, in lesion distribution (more inflammation in the brain relative to the spinal cord), although not all of the features of the human disease are recapitulated. Here we outline the arguments for a possible role for CD8⁺ T cells, a lymphocyte subset that has long been underrated in multiple sclerosis and should now be considered in new therapeutic approaches.