| Summary: | <p style="text-align:justify;"> The intestine and skin are distinct microenvironments with unique physiological functions and are continually exposed to diverse environmental challenges. Host adaptation at these sites is an active process that involves interaction between immune cells and tissue cells. Regulatory T cells (T<sub>reg</sub> cells) play a pivotal role in enforcing homeostasis at barrier surfaces, illustrated by the development of intestinal and skin inflammation in diseases caused by primary deficiency in T<sub>reg</sub> cells. T<sub>reg</sub> cells at barrier sites are phenotypically distinct from their lymphoid-organ counterparts, and these ‘tissue’ signatures often reflect their tissue-adapted function. We discuss current understanding of T<sub>reg</sub> cell adaptation in the intestine and skin, including unique phenotypes, functions and metabolic demands, and how increased knowledge of T<sub>reg</sub> cells at barrier sites might guide precision medicine therapies. </p>
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