CD4+CD25+ regulatory T cells (Treg) constitute an important mechanism of peripheral immune tolerance. Organ-specific autoimmune conditions, such as thyroiditis and insulin-dependent diabetes mellitus have been attributed to a breakdown of this tolerance mechanism. However, this T-cell subset has not been well studied in patients and mice with systemic lupus erythematosus (SLE; lupus). The information that has been gathered so far using new tools that discriminate Treg from activated T cells indicates that reduced numbers of Treg may exist in patients with lupus. In addition, potential defects in SLE Treg function have been documented in humans and mice. Our group has demonstrated equivalent proportions of thymic Treg in lupus prone and normal mice. We therefore propose that Treg function in SLE is the more important factor to address in future studies of murine lupus. Recent studies have shown that Toll-like receptor (TLR) ligation can result in an abrogation of Treg-mediated suppression; specifically ligation of TLR-2, -4, -8 and -9. We address this new information about TLRs and Treg and propose a model for Treg tolerance breakdown to nucleic acid-binding SLE autoantigens.