Summary: As self-recognition is fundamental to the efficient operation of the immune system, a number of mechanisms have evolved to keep this potential pathologic self-reactivity in check. Thus, even though the majority of strongly self-reactive T cells are deleted in the thymus during T-cell maturation, a number of mature T cells that recognize self-antigens can be found in the peripheral circulation in healthy individuals as well as in patients with autoimmune disease. These self-reactive cells are kept in a non-responsive state in healthy individuals while they appear to be involved in the etiology of a number of autoimmune diseases in patients. The primary role of a relatively recently identified T-cell population, referred to as natural CD4+CD25+ regulatory T cells, is to modulate the activity of these self-reactive cells. Although it is still unclear how these regulatory cells function, they can inhibit the activation of other potentially pathologic T cells in in vitro assays. Using such assays, regulatory T cells isolated from patients with a number of autoimmune diseases have been shown to exhibit reduced inhibitory function as compared with those isolated from healthy individuals. In this review, we discuss human natural regulatory T cells, what is known about their function, and their associations with specific autoimmune diseases.