Since LPS was discovered, all inquiry in the field was motivated by two articles of faith. First, it was held that LPS was an important factor in microbial pathogenesis. Second, it was held that the responses elicited by numerous molecules of microbial origin might be formally similar to the responses elicited by LPS. The identification of TLR4 as the core transducer of LPS responses, and the added discovery that other TLR paralogs sense other microbial products, has strongly validated these cherished beliefs. Moreover, it has amalgamated many separate lines of inquiry, and focused attention on the how the innate immune system perceives infection.