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Natural killer T (NKT) cells are an unusual subset of innate immune cells that express a surface receptor generated by somatic DNA rearrangement, a hallmark of cells of the adaptive immune system. NKT cells express a highly restricted repertoire of T cell receptors that recognize glycolipid antigens bound with the antigen-presenting molecule CD1d. A hallmark of NKT cells is their capacity to produce copious amounts of immunomodulatory cytokines upon antigenic stimulation, which endows these cells with potent immunoregulatory properties. Consequently, NKT cells have been implicated in regulating a wide variety of immune responses, including immune responses against autoantigens. In patients and mice with a variety of autoimmune diseases, numbers and functions of NKT cells are disturbed, but the relevance of these findings to the etiology of autoimmunity remains to be fully established. Nevertheless, in some mouse models of autoimmunity, NKT cell-deficiency exacerbates disease, suggesting that NKT cells play a role in suppressing autoimmunity. Conversely, specific activation of NKT cells with glycolipid antigens generally protects mice against the development of autoimmunity. Most of these studies have employed the potent sponge-derived NKT cell antigen alpha-galactosylceramide (alpha-GalCer). However, alpha-GalCer treatment in mice was associated with detrimental side effects and treatment efficacy was influenced by a variety of parameters, resulting sometimes in disease exacerbation rather than protection. Recent efforts have focused on developing NKT cell agonists with superior treatment efficacy than alpha-GalCer. Collectively, these studies have identified NKT cells as attractive targets for treatment of human autoimmune diseases.