Adaptive immunity, as defined by the presence of lymphocytes with rearranged antigen receptors of near infinite specificity, is a characteristic of organisms that carry complex populations of microbial symbionts upon their mucosal surfaces. One might speculate that the coevolution between the adaptive immune system and commensal microbiota was primarily driven by the difficulty of maintaining and controlling such a complex relationship. However, barrier surfaces are not static and are often perturbed by environmental or infectious challenges, causing changes to the commensal microbiota and increasing tissue permeability. In Westernized countries, increased use of antibiotics, reduced worm infections, and drastic changes in nutrition have imposed massive changes in our relations with these organisms. Our understanding of commensal–immune interactions under these highly fluctuating circumstances is still in its infancy and much remains to be understood about commensal-specific responses and their consequences for human health.