Systemic lupus erythematosus is a chronic, multifactorial autoimmune disease of complex etiology, characterized by loss of tolerance to nuclear autoantigens, expansion of autoreactive T and B cell clones, polyclonal B cell activation that gives rise to hypergammaglobulinemia, and increased autoantibody production, as well as immune complex deposition and multiorgan tissue inflammation. As disease progresses, immune cells, mainly T cells and macrophages, infiltrate affected organs and amplify the local inflammatory response. Natural killer cells are large, granular lymphocytes that are an important link between the innate and adaptive immune systems; variations in their activity correlate with several autoimmune diseases. To date, the literature has disregarded natural killer cells as relevant modulators in systemic lupus erythematosus pathogenesis, as these cells are few in number and show a dysfunctional phenotype in patients with active systemic lupus erythematosus. This review focuses on research that could help define the role of natural killer cells in systemic lupus erythematosus and their function in regulating this autoimmune disorder in nonlymphoid organs.