Regulatory T cells (T(reg)) control an array of immune responses both in the context of various polarized settings as well as in distinct microenvironments. This implies that maintenance of peripheral homeostasis relies on the capacity of T(reg) to appropriately adapt to these defined settings while sustaining a regulatory program in the face of inflammation. Adaptation of T(reg) is particularly critical in tissues constantly exposed to microbes, such as the gut or the skin, or in the context of exposure to pathogenic microbes. Recent evidence supports the idea that the capacity of T(reg) to control defined polarized settings can be associated with the acquisition of specific transcription factors previously associated with effector T-cell lineages. In this review we will discuss how such adaptation of T(reg) can have a major role in the control of host-microbe interaction.