The inflammatory response to microbes--and host perception of microbes in general--is largely initiated by a single class of receptors, named for their similarity to the prototypic Toll receptor of Drosophila. The mammalian Toll-like receptors (TLRs) are ultimately responsible for most phenomena associated with infection. This includes both "good" effects of infection (e.g., the induction of lasting specific immunity to an infectious agent) and "bad" effects of infection (systemic inflammation and shock). Although they are essential for host defense, no other endogenous proteins can match their lethal potential. The TLR complexes transduce the toxicity of lipopolysaccharide (LPS), cysteinyl lipopeptides, and many other molecules of microbial origin. The identification of the TLRs as the key conduit to host awareness of microbial infection was a victory for reductionism, proving that the complexity of infectious inflammation as a phenomenon belies the simplicity of its origins. It was achieved by a classical genetic approach, proceeding from phenotype to gene. Further analysis of the signaling pathways activated by the TLRs has depended on both classical and reverse genetic methods. Additional work will ultimately disclose the extent to which sterile inflammatory diseases are mediated by aberrations in these pathways.