It is now widely accepted that the normal immune system harbors a regulatory T-cell population specialized for immune suppression. It was found initially that some CD4+ T cells in normal animals were capable of suppressing autoimmunity. Characterization of this autoimmune-suppressive CD4+ T cell population revealed that they constitutively expressed the CD25 molecule, which made it possible to distinguish them from other T cells, delineate their developmental pathways, in particular their thymic development, and characterize their potent in vivo and in vitro immunosuppressive activity. The marker also helped to identify human regulatory T cells with similar functional and phenotypic characteristics. Recent studies have shown that CD25+CD4+ regulatory T cells specifically express the transcription factor Foxp3. Genetic anomaly of Foxp3 causes autoimmune and inflammatory disease in rodents and humans through affecting the development and function of CD25+CD4+ regulatory T cells. These findings at the cellular and molecular levels altogether provide firm evidence for Foxp3+CD25+CD4+ regulatory T cells as an indispensable cellular constituent of the normal immune system and for their crucial roles in establishing and maintaining immunologic self-tolerance and immune homeostasis. They can be exploited for clinical use to treat immunological diseases and control physiological and pathological immune responses.