Beutler is best known for his pioneering molecular and genetic studies of inflammation and innate immunity. Interested in the mechanism by which lipopolysacchride (LPS) activates mammalian immune cells, Beutler identified the LPS receptor. Identification of the receptor hinged on the positional cloning (a method of gene identification) of the mammalian "Lps" locus, which had been known since the 1960s as a key gene for biological responses to LPS.