Tissue maintenance and homeostasis can be achieved through the replacement of dying cells by differentiating precursors or self-renewal of terminally differentiated cells or relies heavily on cellular longevity in poorly regenerating tissues. Regulatory T cells (T_reg cells) represent an actively dividing cell population with critical function in suppression of lethal immune-mediated inflammation. The plasticity of T_reg cells has been actively debated because it could factor importantly in protective immunity or autoimmunity. By using inducible labeling and tracking of T_reg cell fate in vivo, or transfers of highly purified T_reg cells, we have demonstrated notable stability of this cell population under physiologic and inflammatory conditions. Our results suggest that self-renewal of mature T_reg cells serves as a major mechanism of maintenance of the T_reg cell lineage in adult mice.