Recent years have seen a dramatic improvement in our understanding of the role of innate immunity, and particularly Toll-like receptor (TLR) signaling, in human host defense. Appreciation of how defects in human TLR signaling enhance susceptibility to infection began with the identification of patients with monogenic immunodeficiencies, such as hypohydrotic ectodermal dysplasia with immunodeficiency and IRAK4 deficiency. Empowered by technological advances in genotyping and bioinformatics, we are now beginning to appreciate how common genetic variation in the genes controlling the innate immune response alters infectious susceptibility in a subtle but specific fashion. This review highlights the mechanisms of infectious susceptibility that result from complex interactions between the genetically variable host and microbe and explores how this new knowledge may ultimately translate into better care for our patients.