Transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) are regulatory cytokines with pleiotropic roles in the immune system. The prominent function of TGF-β is to maintain T cell tolerance to self or innocuous environmental antigens via its direct effects on the differentiation and homeostasis of effector and regulatory T cells. A critical route for the regulation of T cells by TGF-β is via activation of a T cell-produced latent form of TGF-β1 by dendritic cell-expressed avβ8 integrin. IL-10 operates primarily as a feedback inhibitor of exuberant T cell responses to microbial antigens. T cells are also the principal producers of IL-10, the expression of which is regulated by IL-27, IL-6, and TGF-β. The collective activity of TGF-β and IL-10 ensures a controlled inflammatory response specifically targeting pathogens without evoking excessive immunopathology to self-tissues.