Apart from the deletion of autoreactive T cells in the thymus, various methods exist in the peripheral immune system to control specific human immune responses to self-antigens. One of these mechanisms involves regulatory T cells, of which CD4+CD25+ T cells are a major subset. Recent evidence suggests that CD4+CD25+ T cells have a role in controlling the development of autoimmune diseases in animals and in humans. The precise delineation of the function of CD4+CD25+ T cells in autoimmune inflammation is therefore of great importance for the understanding of the pathogenesis of autoimmune diseases. Moreover, the ability to control such regulatory mechanisms might provide novel therapeutic opportunities in autoimmune disorders such as rheumatoid arthritis. Here we review existing knowledge of CD4+CD25+ T cells and discuss their role in the pathogenesis of rheumatic diseases.