Natural killer (NK) cells were once regarded as relatively simple cells of the innate immune system. However, they are now revealing themselves as multifunctional regulatory cells that are present throughout the body. The role of NK cells in autoimmunity is attracting increased attention, although the picture is clouded by a conflicting literature that presents disease-promoting as well as disease-protective roles. In this review, we discuss how NK cells might use these dual roles, and suggest that future studies should focus on the impact of the anatomical localization of NK cells as well as the cytokine environment in which NK cells act in individual autoimmune diseases.