Any scientist opening up an immunology journal today will observe immediately that suppressor T cells, renamed ‘regulatory T cells’ (Tregs) have become a central concept in the immunology lexicon. Hundreds of Treg publications over the past few years have validated the existence of this unique T cell lineage armed with an ability to regulate autoimmunity. The CD4⁺CD25⁺Foxp3⁺ Treg subset develops in the thymus, can be induced in the periphery during the course of normal immune responses and utilizes a T cell repertoire skewed towards autoantigens. Despite these advances, however, there is still controversy over their mechanism of action. This confusion stems from the differences observed in in vitro versus in vivo studies. Recent in vivo analyses support a model in which Tregs directly or indirectly alter the activation and differentiation of pathogenic T cells through an effect on antigen presenting cells.