The mammalian immune system discriminates among microbes, inactivating pathogens while tolerating colonization by commensal organisms. Calibrating immune responses to microbes on this basis, however, is complex, as microbial virulence is often context dependent, being influenced by the host's immune status and the microbial milieu. Many microbial pathogens infecting immunocompromised hosts, for example, are innocuous in immune-competent individuals, and other microbes cause disease only when the commensal flora is compromised by antibiotic therapy. Recent studies have begun to reveal how the immune system tips the balance in favor of some microbes, allowing commensals to persist on mucosal surfaces while eliminating disease-causing pathogens.