A paradigm shift in immunology has been the recent discovery of regulatory T cells (T reg cells), of which CD4⁺Foxp3⁺ cells are proven as essential to self-tolerance. Using transgenic B6.Foxp3^hCD2 mice to isolate and ablate Foxp3⁺ T reg cells with an anti-hCD2 antibody, we show for the first time that CD4⁺Foxp3⁺ cells are crucial for infectious tolerance induced by nonablative anti–T cell antibodies. In tolerant animals, Foxp3⁺ T reg cells are constantly required to suppress effector T cells still capable of causing tissue damage. Tolerated tissue contains T cells that are capable of rejecting it, but are prevented from doing so by therapeutically induced Foxp3⁺ T reg cells. Finally, Foxp3⁺ cells have been confirmed as the critical missing link through which infectious tolerance operates in vivo. Peripherally induced Foxp3⁺ cells sustain tolerance by converting naive T cells into the next generation of Foxp3⁺ cells. Empowering Foxp3⁺ regulatory T cells in vivo offers a tractable route to avoid and correct tissue immunopathology.