Murine models show that natural killer (NK) cells affect autoimmunity through several potential mechanisms. (a) NK cells limit viral-induced tissue damage by directly killing virally infected cells or by releasing cytokines that can suppress viral propagation either directly or indirectly by activating other cells such as macrophages. Defective NK cell responses to viral infections may result in autoimmunity in genetically predisposed strains of mice as a result of uncontrolled infection leading to increased tissue destruction, with accompanying exposure of self antigens. (b) NK cells participate in the immunoregulation of other immune cells. Control of autoreactive T and B cells by NK cells may be mediated directly through the release of cytokines and chemokines or indirectly through bidirectional interactions with other components of the innate immune system such as dendritic cells (DCs). In addition, it is possible that NK cells may kill autoreactive lymphocytes or inappropriately activated immature DCs. (c) NK cells could potentially mediate an autoimmune response by inappropriately killing normal tissues.