TGF-beta and CD4+CD25+ regulatory T cells (Treg) both play an important role in the control of immune responses and the maintenance of immune homeostasis. The mechanism of suppression induced by Treg and the factors which regulate Treg function and number, have only begun to be elucidated. TGF-beta seems to act as an effector cytokine involved in the immunosuppressive function of Treg in vitro and in vivo, although its origin and mechanism of action remains to be defined. In addition, TGF-beta signaling in peripheral Treg seems to be essential for the regulation of peripheral Treg numbers and for their immunosuppressive function in vivo. This review will focus on the role of TGF-beta for the generation and expansion of CD4+CD25+ Treg, as well as for their immunosuppressive function in vitro and in vivo.