The microbiota-the diverse set of commensal microbes that normally colonize humans-represents the first line of defense against infectious diseases. In this review, we summarize the direct and indirect mechanisms by which the microbiota modulates susceptibility to, and severity of, infections, with a focus on immunological mechanisms. Moreover, we highlight some of the ways that modern-world lifestyles have influenced the structure-function relationship between the microbiota and infectious diseases. Ultimately, understanding how the microbiota influences infectious risks will facilitate development of microbiota-derived therapeutics that bolster host defenses.