Foxp3+ regulatory T (Treg) cells are essential for maintaining self-tolerance and preventing autoimmune reactions. Treg cells arise as a consequence of self-antigen recognition during the maturation of cells in the thymus, and also following self-antigen recognition in the periphery. Both thymic and peripherally generated Treg cells respond to antigen recognition by expanding in number, increasing their suppressive activity, and accumulating in the tissue where the antigen is located. A fraction of these activated “effector” Treg cells survive even in the absence of antigen expression and continue to control inflammatory reaction in the tissues, thus functioning as a population of “memory” Treg cells. Antigen exposure and the presence of IL-2 are key determinants in the generation of memory Treg cells. These results provide a foundation for studying the role of memory Treg cells in controlling and treating autoimmune disorders and for testing the hypothesis that defects in the generation and maintenance of these cells underlie chronic, relapsing inflammatory diseases.