Immunological self tolerance is maintained at least in part by regulatory T (T(reg)) cells that actively and dominantly control potentially hazardous self-reactive T cells in the periphery. Antigens that stimulate self-reactive T cells may also activate natural T(reg) cells, thereby maintaining dominant self tolerance. Conversely, genetic anomalies or environmental agents that specifically or predominantly affect T(reg) cells cause or predispose to autoimmunity. With recent advances in our understanding of T(reg) cell development in the thymus and periphery and the molecular mechanism of T(reg) cell-mediated suppression, new ways of treating immunological diseases by targeting T(reg) cells at the cellular and molecular levels are envisaged.