Natural CD4⁺CD25⁺ regulatory T cells (T_reg) show a potent immunosuppressive function and contribute to immunologic self-tolerance by suppressing potentially auto-reactive T cells. Depletion of these cells leads to the induction of severe autoimmune diseases in animal models; more recently, several studies have also reported an impairment of T_reg number and/or function in various human autoimmune diseases. For example, aberrant numbers of circulating CD4⁺CD25⁺ T_reg have been seen in patients with type I diabetes, mycosis fungoides, graft-versus-host-reaction, and rheumatoid arthritis. Moreover, increased numbers of functionally active CD4⁺CD25⁺ T_reg have been detected in the synovial fluid of patients with rheumatoid arthritis. In systemic lupus erythematosus (SLE), conflicting data on the role of CD4⁺CD25⁺ T_reg in human autoimmune diseases have been presented in the literature. Decreased numbers of peripheral blood T_reg have been reported by most studies on SLE patients with active disease, but non-impaired or even increased CD4⁺CD25⁺ T_reg numbers have also been described. In addition, both deficient and normal suppressive capacity of isolated T_reg have been observed in SLE. Analysis of CD4⁺FoxP3⁺ T_reg in skin lesions of patients with a primarily cutaneous manifestation of the disease showed a significant reduction in cell numbers as compared to other inflammatory skin diseases, suggesting the importance of analyzing T_reg numbers in the affected tissue. In this review, we discuss the role of CD4⁺CD25⁺ T_reg in autoimmunity and recent published data on SLE. Furthermore, we highlight the need for additional studies that address specific gaps of knowledge regarding the pathophysiological mechanisms as well as the identification of future therapeutic strategies for autoimmune diseases.