Suppressor T cells were first described in the early 1970s, but since the hypothetical soluble suppressor factor could not be identified on a molecular level and since appropriate cellular markers were lacking, the suppressor T cell concept vanished for a long time. The discovery by Sakaguchi and co-workers, that the adoptive transfer of CD25+CD4+ -depleted T cells induced several organ-specific autoimmune diseases in immunodeficient recipients, put the suppressor T cell model back into the focus of many immunologists. CD25+CD4+ T cells were named regulatory T cells (Treg) and since then have been intensively characterized by many groups. It has now been well documented in a variety of models that CD25+CD4+ Tregs, in addition to cell-intrinsic peripheral tolerance mechanisms such as anergy induction and peripheral deletion, play indispensable roles in the maintenance of natural self-tolerance, in averting autoimmune responses as well as in controlling inflammatory reactions. However, a number of fundamental questions concerning their origin, mechanism of action, and the sites of suppression remain elusive and are currently a matter of debate. Notably, the potential heterogeneity of Tregs with respect to phenotype and function deserves attention and is a major issue discussed in this review.