The body is composed of various tissue microenvironments with finely tuned local immunosurveillance systems, many of which are in close apposition with distinct commensal niches. Despite our growing understanding of the ramifications imposed by this host-microbe alliance on immunity, the degree to which individual microenvironments are controlled by resident microbiota remains unclear. We will discuss how outside of the gastrointestinal (GI) tract, resident commensals can control unique physiological niches and the potential implication of this dialogue for the establishment of immune homeostasis, protective responses and tissue pathology.