The Toll-like receptors (TLRs) are the key proteins that allow mammals--whether immunologically naive or experienced--to detect microbes. They lie at the core of our inherited resistance to disease, initiating most of the phenomena that occur in the course of infection. Quasi-infectious stimuli that have been used for decades to study inflammatory mechanisms can activate the TLR family of proteins. And it now seems that many inflammatory processes, both sterile and infectious, may depend on TLR signalling. We are in a good position to apply our understanding of TLR signalling to a range of challenges in immunology and medicine.