Mouse lymphoid tissues contain a subset of dendritic cells (DCs) expressing CD8α together with a pattern of other surface molecules that distinguishes them from other DCs. These molecules include particular Toll‐like receptor and C‐type lectin pattern recognition receptors. A similar DC subset, although lacking CD8 expression, exists in humans. The mouse CD8⁺ DCs are non‐migrating resident DCs derived from a precursor, distinct from monocytes, that continuously seeds the lymphoid organs from bone marrow. They differ in several key functions from their CD8⁻ DC neighbors. They efficiently cross‐present exogenous cell‐bound and soluble antigens on major histocompatibility complex class I. On activation, they are major producers of interleukin‐12 and stimulate inflammatory responses. In steady state, they have immune regulatory properties and help maintain tolerance to self‐tissues. During infection with intracellular pathogens, they become major presenters of pathogen antigens, promoting CD8⁺ T‐cell responses to the invading pathogens. Targeting vaccine antigens to the CD8⁺ DCs has proved an effective way to induce cytotoxic T lymphocytes and antibody responses.