It is now well recognized that regulatory T cells (Treg) play a central role in the control of both reactivity to self-antigens and alloimmune response. Several subsets of Treg with distinct phenotypes and mechanisms of action have now been identified. They constitute a network of heterogeneous CD4+ or CD8+ T cell subsets and other minor T cell populations such as nonpolymorphic CD1d-responsive natural killer T cells. Treg not only play a main role in maintaining self-tolerance and preventing autoimmune disease but can also be induced by tolerance protocols and seemed to play a key role in preventing allograft rejection, as demonstrated in many animal models. Of particular interest, in stable transplant patients, CD4+CD25+ and CD8+CD28- Treg have been recently shown to modulate immune response toward donor antigens in the indirect and direct pathway, respectively. This finding raises the possibility that such Treg also have a role in the induction or maintenance of transplant tolerance in humans.