Natural T regulatory cells (NatTReg) limit immunopathology and protective immune responses induced upon microbial infection. In addition, infection increases the number and activity of NatTReg. These findings need to be conciliated with the process of 'self-nonself' discrimination based on the function of NatTReg committed intrathymically and positively selected (and activated) on thymic epithelial cells. A review of the available evidence comforts the assumptions that, in physiological conditions, NatTReg engaged in the immune responses to microbial infections are drawn from the autoreactive repertoire even if some may appear to be microbe specific. This contention also provides a suitable explanation for the 'hygiene hypothesis': infections re-enforce the physiological mechanisms of natural dominant tolerance, through the expansion of naturally occurring regulatory T cells. Accumulating evidence demonstrates that pro-inflammatory ligands of Toll-like receptors expressed by NatTReg, both of microbial (e.g., lipopolysaccharide, flagellin, peptidoglycans) and endogenous (e.g., stress proteins and degradation products of the extracellular matrix) origin, may play a critical role in their activation and expansion. As NatTReg vigorously respond to IL-2/IL-15 locally produced by ongoing effector responses, this whole set of mechanisms provides for a robust feedback process that limits tissue damage and accounts for an 'organism-centered' quality control of immune responses. Detailed knowledge on these molecular and cellular bases should open novel opportunities for intervention in a variety of critical conditions, such as autoimmunity, allergy, chronic infections, and cancer, for which we currently lack effective therapies.