Maintenance of immune tolerance in the periphery can be envisioned as a balance between autoreactive lymphocytes and regulatory mechanisms that counteract them. The naturally occurring CD4⁺CD25⁺ regulatory T cells (T_REGs) have a major role in modulating the activity of self-reactive cells. The identification of Forkhead box P3 transcription factor (FoxP3) as the critical determinant of T_REG development and function has provided new opportunities and generated expanded interest in studying the balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. The identification of both human and mouse diseases resulting from the lack of FoxP3 expression, and consequently the absence of T_REGs, has rapidly expanded knowledge of T_REG development and function during the past 5 years. Although it is still unclear how these regulatory cells function, they can inhibit the activation of potentially pathogenic T cells in vitro. Using in vitro functional assays and phenotypic analysis, T_REGs isolated from patients with a variety of autoimmune diseases have been shown to exhibit reduced regulatory function as compared with those isolated from healthy controls. This Review will focus on the current state of knowledge on human T_REGs and their association with specific autoimmune diseases.