Collectively, the mammalian Toll‑like receptors (TLRs) sense host invasion by most microbes, including bacteria, fungi, protozoa, and viruses. They do so by recognizing signature molecules that herald infection: lipopeptides, lipopolysaccharides, flagellin, dsRNA, ssRNA and ssDNA. When such ligands engage TLRs, a conformational change is elicited leading to signaling via a chain of adaptor proteins, kinases, and ubiquitin ligases that ultimately cause the activation of transcription factors, including NF‑κB, AP‑1, and the IRFs. These transcription factors activate hundreds of genes, many of them encoding cytokines, and also change the entire cellular milieu. Other signaling events permit augmented translation of mRNAs encoding specific cytokines. Once released, the cytokines drive the inflammatory response that is usually witnessed in the setting of infection. It is remarkable that so few TLRs, and so few inciting molecules, are capable of initiating the inflammatory response to infection, with its myriad consequences. Moreover, the fact that similar signaling pathways are triggered by diverse microbes accounts for similarities in the mammalian response to many different kinds of infection. The role of TLRs in sterile inflammation, including certain autoimmune diseases, has begun to gain clarity with the recognition that endogenous nucleic acids can be detected by TLRs. In this sense, some kinds of autoimmunity may be viewed as a consequence of the limited resolving power of innate immune receptors.