The well-being of the intestine and its host requires that this organ execute its complex function amid colonization by a large and diverse microbial community referred to as the gut microbiota. A myriad of interacting mechanisms of mucosal immunity permit the gut to corral the microbiota in such a way as to maximize the benefits and to minimize the danger of living in close proximity to this large microbial biomass. Toll-like receptors and Nod-like receptors, collectively referred to as pattern recognition receptors (PRRs), recognize a variety of microbial components and, hence, play a central role in governing the interface between host and microbiota. This review examines mechanisms by which PRR-microbiota interactions are regulated so as to allow activation of host defense when necessary while preventing excessive inflammation, which can have a myriad of negative consequences for the host. Analysis of published studies performed in human subjects and a variety of murine disease models reveals the central theme that PRRs play a key role in maintaining a healthful stable relationship between the intestine and its microbiota. In contrast, although select genetic ablations of PRR signaling may protect against some chronic diseases, the overriding theme of studies performed to date is that perturbations of PRR-microbiota interactions are more likely to promote disease states associated with inflammation.