The immune system requires a homeostatic equilibrium between the mechanisms that assure self-tolerance, those that control the capacity to mount life-long immunity to pathogenic microbes, and those that attenuate effector mechanisms from inducing immune pathology [Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell 2008, 133 (5):775-87; Piccirillo CA, Thornton AM: Cornerstone of peripheral tolerance: naturally occurring CD4+CD25+regulatory T cells. Trends Immunol 2004, 25:374-80]. In the past decade, an overwhelming body of literature showed that CD4+Foxp3+ regulatory T (Treg) cells are a dominant mechanism regulating the decision fate of these different immunological outcomes. Indeed, CD4+Foxp3+ Treg cells develop largely in the thymus but can be induced in the periphery throughout the course of immune responses [Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell 2008, 133 (5):775-87; Piccirillo CA, Thornton AM: Cornerstone of peripheral tolerance: naturally occurring CD4+CD25+regulatory T cells. Trends Immunol 2004, 25:374-80]. Treg cells have emerged as a central control point in the regulation of autoimmune responses. Despite progress made in various in vitro and in vivo models, much uncertainty exists over their mechanism of action in vivo. Here, we summarize research characterizing the functional dynamics of CD4+Foxp3+ Treg cells in the control of autoimmunity in rodents and humans.