Regulation of the immune response to self-antigens is a complex process that depends on maintaining self-tolerance while retaining the capacity to mount a robust immune response to foreign antigens. Autoreactive T cells specific for these autoantigens are present in most normal individuals but are kept under control by multiple diverse peripheral tolerance mechanisms. In the last few years, there has been a re-emergence of suppressor cells as among the most central of these regulatory mechanisms. These cells, which express CD4, CD25, and CD62L, develop in the thymus and survive in a CD28-dependent manner in the periphery to maintain the homeostatic equilibrium of immunity and tolerance. In this review, we will summarize studies of these regulatory cells as they relate to autoimmune diseases and more specifically to type 1 diabetes and attempt to address some of the many outstanding questions. Finally, evidence is provided to support the ability of anti-CD3 mAbs to stimulate the regulatory T cells and reset the rheostat of immune tolerance in an animal model of autoimmune diabetes, the NOD mouse.