The subset of CD4⁺ T lymphocytes that coexpress high levels of the interleukin (IL)-2 a receptor and the transcription factor Foxp3  (CD4⁺CD25^highFoxp³⁺ cells), commonly called regulatory T cells (Tregs), have a key role in the mechanisms of peripheral immune tolerance. Tregs modulate innate and adaptive immune responses in vitro and in vivo by suppressing the proliferation and cytokine production in different subsets of immune cells. Their key role in autoimmunity is suggested by the finding that reconstitution of normal numbers and/or function of Tregs in autoimmune animals associates with a delay of disease development and progression, whereas the elimination of Tregs can anticipate or precipitate disease. Since naturally occurring ("natural") Tregs represent only a small fraction of peripheral blood, the investigations for possible therapeutic use of Tregs in autoimmunity has largely focused on the use of "adaptive" Tregs, which can be induced through several different modalities. This review discusses the role of natural Tregs in the suppression of autoimmune responses and the relevance of these cells for possible therapeutic applications in autoimmunity.