A network of regulatory T (Treg) cells exists to downregulate immune responses in various inflammatory circumstances and ultimately assure peripheral T cell tolerance. Naturally occurring CD4(+)CD25(+) Treg cell represents a major lymphocyte population engaged in the dominant control of self-reactive T responses and maintenance of tolerance within this network. CD4(+)CD25(+) Treg cells differentiate in the normal thymus as a functionally distinct subpopulation of T cells bearing a broad T cell receptor repertoire endowing these cells with the capacity to recognize a wide spectrum of self-Ag and non-self-Ag specificities. The development of CD4(+)CD25(+) Treg cells is genetically determined, influenced by Ag-specific and nonspecific signals, costimulation, and cytokines that control their activation, expansion, and suppressive activity. Functional abrogation of these cells in vivo, or genetic defects that affect their development or function, unequivocally predisposes animals and humans to the onset of autoimmune and other inflammatory diseases. Studies have shed light in our understanding of the cellular and molecular basis of CD4(+)CD25(+) Treg cell-mediated immune regulation. In this chapter, we discuss the contribution of naturally occurring CD4(+)CD25(+) Treg cells in the induction of immunologic self-tolerance in animal models and humans and attempt to provide a comprehensive overview of recent findings regarding the phenotype, functional dynamics, and effector mechanism of these cells in autoimmune diseases.