Despite the tremendous interindividual variability in the response to toxins, we simply do not understand why certain people have disease develop when challenged with toxic agents, and why others remain healthy. To address this concern, we investigated whether the TLR-4 gene (toll-like receptor [TLR]4), which has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, underlies the variability in airway responsiveness to inhaled LPS in humans. Here we show that common, cosegregating missense mutations (Asp299Gly and Thr399Ile) in the extracellular domain of the TLR4 receptor are associated with a significantly blunted response to inhaled LPS in 83 humans. Although in vitro findings confirm these in vivo observations, our results in humans also indicate that genes other than TLR4 may be playing a role in the biological response to LPS. To pursue this possibility, we studied genetically diverse inbred strains of mice, as well as recombinant inbred strains of mice, and have found that although TLR4 is clearly important in directing the biological response to LPS, additional genes are clearly involved in determining the physiologic and biological response to LPS in mammals.