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That is because their primary genetic associations are mostly with certain human leukocyte antigen class II alleles, whose gene products present antigens to CD4<jats:sup>+<\/jats:sup> T cells. Because few autoimmune diseases show stronger associations with major histocompatibility complex class I alleles (ankylosing spondylitis, Beh\u00e7et's disease, and psoriasis), CD8<jats:sup>+<\/jats:sup> T cells, which interact with major histocompatibility complex class I molecules, have been largely ignored in autoimmunity research. However, a variety of findings has recently revived interest in this population, particularly in MS. First, it shows associations with major histocompatibility complex class I alleles. Second, its lesions show a predominance of CD8<jats:sup>+<\/jats:sup> T cells. Third, these represent effectors that can directly damage central nervous system target cells. Furthermore, several clinical trials of monoclonal antibodies specifically against CD4<jats:sup>+<\/jats:sup> T cells, or the polarizing cytokines on which they depend, have failed to show any therapeutic benefit in MS, unlike broader\u2010spectrum antibodies that deplete all T cells. Here, we review the evidence that CD8<jats:sup>+<\/jats:sup> T cells play a role in MS pathogenesis. 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