Autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis (RA) are characterized by the breakdown of immunological tolerance. Defects of regulatory T cells have been described among the various mechanisms, that are important for the development of autoimmune diseases, due to their critical role as regulators of peripheral immune tolerance and homeostasis. Initially T suppressor cells have been described as one population of peripheral T cells. Based on new technological advances a new understanding of the heterogeneity of different Treg cell populations in the lymphoid and non-lymphoid tissue has evolved over the last years. While initially Foxp3 has been defined as the main master regulator of Treg cells, we have learned that Treg cells from various tissue can be identified by a specific transcriptomic and epigenetic signature. Epigenetic mechanisms allow Treg cell stability, but we have also learned that certain Treg subsets are plastic and can under specific circumstances even enhance autoimmunity and inflammatory processes. Quantitative and functional defects of Treg cells have been observed in a variety of autoimmune diseases. Due to our understanding of the nature of this cell population, Treg cells have been a target of new Treg based therapies, such as low-dose IL-2. In addition, ongoing clinical trials aim to test safety and efficacy of transferred, in vitro expanded Treg cells in patients with autoimmune diseases and transplant patients.