Tolerogenic antigen-presenting cells (APCs) are attractive agents for the treatment of autoimmune and inflammatory diseases that are mediated, at least in part, by antigen-specific autoreactive T cells. Transforming growth factor-beta (TGF-beta)-treated antigen-presenting cells induce a very potent form of tolerance in mice. One unique feature of this simple and elegant method of tolerance induction is that it is equally potent in both primed and naive mice, an important consideration for the development of a therapy that will be effective against an established disease. In this model, F4/80+ peritoneal exudate cells (macrophages) cultured with antigen and TGF-beta2 injected iv induce populations of regulatory T cells that mediate long-lasting antigen-specific tolerance in mice. The mechanisms that are involved in the induction of tolerance by TGF-beta-treated APCs are very complex and require the interaction of a variety of cell types, as well as soluble and membrane-bound factors. In this review, we summarize the existing data and present new data concerning the induction and effector mechanisms associated with TGF-beta-treated APC-induced tolerance. An understanding of these mechanisms will provide very important information for the design of effective strategies for the treatment of a variety of diseases that are mediated by pathogenic T cells.