The vertebrate immune system consists of two inter-related components, the innate and adaptive responses, which are required for the resolution of infection. The innate immune response is critical for the immediate protection from infection and for marshalling the B- and T-cell responses of the adaptive response. A key component of the innate immune response is germline-encoded pattern recognition receptors that detect pathogens. Several families of these pattern recognition receptors have now been described. Microbial recognition by these receptors triggers appropriate immune responses, including the direct uptake and killing of pathogens and/or initiation of intracellular signaling pathways that culminate in the activation of immune responsive transcriptional programs. Pattern recognition receptors include soluble receptors in serum (collectins), transmembrane receptors on cell surfaces or vacuolar membranes (C-type lectins and Toll-like receptors) or cytoplasmic sensors (NACHT-LRR proteins and RNA helicases). Roles for these pattern recognition receptor families are emerging in the susceptibility to bacterial and viral infections and in acute and chronic conditions, such as sepsis, autoimmune disease and atherosclerosis. These findings suggest that the selective targeting of pattern recognition receptors and the pathways they trigger may be useful clinically. Progress towards therapeutics designed to target Toll-like receptor signaling is already well underway. This review will describe our current understanding of innate immune sensors and the mechanisms regulating their activity.