Cytotoxic T lymphocytes (CTLs) with a CD8⁺ phenotype have the potential to recognize and attack major histocompatibility complex (MHC) class I-expressing brain cells. Most brain cells, including neurons, can be stimulated to present peptides to CD8⁺ CTLs by MHC class I molecules, and are susceptible to CTL-mediated cytotoxicity in culture. In disease-affected brain parenchyma, CD8⁺ CTLs outnumber other T-cell subtypes. They show clonal expansion in several inflammatory and degenerative CNS diseases, such as multiple sclerosis (MS), virus-induced inflammatory brain diseases and paraneoplastic neurological disorders. In MS, damage of axons is closely linked to the CD8⁺ CTLs, and protection against CTL-mediated damage should be considered as a new therapeutic approach in MS and other neuroinflammatory diseases.