How regulatory T (TR) cells dampen T cell responses remains unclear. Multiple modes of action have been proposed, including cell contact-dependent and/or cytokine-dependent mechanisms. Suppression may involve direct contact between TR cells and responder T cells. Alternatively, TR cells may act on dendritic cells to reduce their ability to prime T cells by modulating costimulation, inducing the secretion of suppressive cytokines or the increase of tryptophan metabolism. Here, we review emerging, novel mechanisms involved in contact-dependent, TR-mediated suppression of IL-2 production in responder CD25- T lymphocytes and the potential involvement of inducible cAMP early repressor (ICER) in this suppression. Finally, cytokines such as TGF-beta and IL-10, produced by TR cells or other cells, may exert local suppression, which can be conveyed by basic mechanism(s) acting in a similar manner as contact-dependent, TR-mediated suppression.