CD4 + CD25 + regulatory T (TR) lymphocytes are essential to the maintenance of immunologic tolerance in the host. The discovery of Foxp3 as a transcription factor essential to the differentiation of TR ushered in detailed studies of the molecular mechanisms of TR cell development, peripheral homeostasis, and effector functions. In humans, loss of function mutations in genes that regulate T-cell development and function have been associated with TR cell deficiency or dysfunction and syndromes of autoimmunity and immune dysregulation. Augmentation of TR cells by immunotherapy and pharmacologic agents is a promising strategy for the treatment of allergic and autoimmune diseases.