Mucosal surfaces, especially those of the gastrointestinal (GI) tract, are sites for tolerance induction to numerous exogenous antigens (Ags), and provide a microenvironment suitable for generating tolerogenic dendritic cells (DCs) that contribute to the functional maturation of regulatory T cells. During immune homeostasis in the GI tract, innate immune signals provided by innocuous or commensal bacteria play important roles in stabilizing this noninflammatory microenvironment and function of regulatory T cells. Thus oral tolerance consists of two phases of immune response: the maintenance of homeostasis and the suppression of immune responses mediated by Ag-specific regulatory T cells. Elucidating mechanisms for both phases should contribute to physiological intervention of local and systemic immunity, thereby improving homeostasis in both health and disease.