Natural killer (NK) cells are evolutionarily early lymphocytes that lack antigen-specific receptors and, hence, are considered to be part of the innate immune system. The majority of research on NK cells has focused on their ability to lyse "target cells", generally identified by low or absent MHC Class I expression, such as tumor cells and virus infected cells. However, an alternative role of these leukocytes as regulators of adaptive (and potentially destructive) immune responses, in particular organ-specific autoimmune diseases, has been increasingly recognized. Here we discuss the growing body of evidence that NK cells limit damage in autoimmune demyelinating disease by inhibiting autoreactive T cell responses without harming resident neurons or glia. (c) 2007 Elsevier B.V. All rights reserved.