The innate immune system plays an essential role in the host's first line of defense against microbial invasion, and involves the recognition of distinct pathogen-associated molecular patterns by pattern recognition receptors (PRRs). Activation of PRRs triggers cell signaling leading to the production of proinflammatory cytokines, chemokines and Type 1 interferons, and the induction of antimicrobial and inflammatory responses. These innate responses are also responsible for instructing the development of an appropriate pathogen-specific adaptive immune response. In this review, the focus is on different classes of PRRs that have been identified, including Toll-like receptors, nucleotide-binding oligomerization domain-like receptors, and the retinoic acid-inducible gene-I-like receptors, and their importance in host defense against infection. The role of PRR cooperation in generating optimal immune responses required for protective immunity and the potential of targeting PRRs in the development of a new generation of vaccine adjuvants is also discussed.