The innate immune system must recognize and rapidly respond to microbial pathogens, providing a first line of host defense. This is accomplished through an array of pattern recognition receptors (PRRs) that reside in specific subcellular compartments and can bind pathogen-associated molecular patterns. PRRs also recognize self-molecules that are released after cell damage or death, known as danger-associated molecular patterns, which can be actively transported across cell membranes. The activation of PRRs leads to host defense pathways in infectious diseases, but can also contribute to tissue injury in autoimmune diseases. The identification of these pathways has provided new insight into mechanisms of vaccination and holds promise for developing better vaccines. Finally, the identification of PRRs, their ligands, and signaling pathways provides an opportunity for developing new immunotherapeutic approaches to skin conditions in which activation of the innate immune response contributes to disease pathogenesis.