Clonal deletion of autoreactive T cells in the thymus is not the sole mechanism for the induction of tolerance to self-antigens since partial depletion of peripheral CD4(+) T cells from neonatal and adult animals results in the development of organ-specific autoimmunity. Reconstitution of these immunodeficient animals with populations of regulatory CD4(+)T cells prevents the development of autoimmunity. The lineage of regulatory CD4(+) T cells is generated in the thymus and can be distinguished from effector cells by the expression of unique membrane antigens. The target antigens for these suppressor populations and their mechanisms of action remain poorly defined. Depletion of regulatory T cells may be useful in the induction of immunity to weak antigens, such as tumor-specific antigens. Conversely, enhancement of regulatory T cell function may be a useful adjunct to the therapy of autoimmune diseases and for prevention of allograft rejection.