Cytotoxic CD8⁺ T cells are increasingly recognized as key players in various inflammatory and degenerative central nervous system (CNS) disorders. CD8⁺ T cells are believed to actively contribute to neural damage in these CNS conditions. Conceptually, one can separate two possible ways that CD8⁺ T cells harm neuronal function or integrity: CD8⁺ T cells either directly target neurons and their neurites in an antigen‐ or contact‐dependent fashion, or exert their action via “collateral” mechanisms of neuronal damage that might follow destruction of the myelin sheath or glial cells in both the CNS gray and white matter. After introducing clinical examples, in which the putative relevance CD8⁺ T cells has been demonstrated, we summarize knowledge on the sequence of initiation and execution of CD8⁺ T‐cell responses in the CNS. This includes the initial antigen cross‐presentation and priming of naive CD8⁺ T cells, followed by the invasion, migration, and target‐cell recognition of CD8⁺ effector T cells in the CNS parenchyma. Moreover, we discuss mechanisms of impaired electrical signaling and cell death of neurons as direct and collateral targets of CD8⁺ T cells in the CNS.—Melzer, N., Meuth, S. G., and Wiendl, H. CD8⁺ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability. FASEB J. 23, 3659–3673 (2009). www.fasebj.org