Mutations of the mouse Lps locus abolish responses to lipopolysaccharide (LPS). Positional cloning work has revealed that Lps encodes the Toll-like receptor 4 (Tlr4), which functions as the transmembrane component of the LPS receptor complex, an unduplicated pathway for the detection of endotoxin. The structurally related protein Tlr2 makes no contribution to LPS signal transduction.