The study of a rare human X-linked disease resulting in a characteristic clinical phenotype of multiple autoimmune disorders and the in-depth exploration of a spontaneous mouse model, scurfy (sf), have contributed to a better understanding of the regulation of immunologic responses, particularly to self. Forkhead box P3 (FOXP3), the gene responsible for IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) and sf is located on the X chromosome and is of crucial importance for the generation of CD4+ CD25+ regulatory T cells. Loss of FOXP3 function and the resultant lack of regulatory T cells result in lethal auto-aggressive lymphoproliferation, whereas overexpression of this modulator results in severe immunodeficiency. The in-depth analysis of FOXP3 regulation and elucidation of the precise mechanisms by which FOXP3 exerts its regulatory effect will provide important insights into the understanding of autoimmunity and should predictably result in new therapeutic possibilities.