Naturally arising CD25+CD4+ regulatory T cells, which express the transcription factor Foxp3, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. The majority of them are produced by the normal thymus as a functionally mature T cell subpopulation specialized for suppressive function. Their generation is in part genetically and developmentally controlled. Genetically determined or environmentally induced abnormality in CD25+CD4+ regulatory T cell development, maintenance, and function can be a cause of autoimmune disease in humans.