The genetic background has recently been recognized as an important element in the response to injury, contributing to the variability in the clinical outcome of critically ill patients. The traditional approach to studying the genetic contribution requires the availability of families with multiple members who have experienced similar disease conditions, a situation that is nearly impossible to find in the case of trauma. Association studies looking at unrelated individuals across populations require large economic and labor-intensive efforts. Thus, a candidate gene approach has been the sole methodology used to correlate genetic variability with clinical outcome. However, this approach cannot provide a comprehensive description of a multigenic condition. Animal models are an alternative for studying the genetic contributions to variability in the response to injury. A murine model is ideal because a large set of inbred strains are available; congenic, consomic, transgenic, and recombinant strains can also be used. Employing this paradigm, we have demonstrated that the response to several stressors, such as injection of E. coli lipopolysaccharide (LPS) and polymicrobial sepsis induced by cecal ligation and puncture (CLP), is modified by the genetic background. The inflammatory response in mice has also been shown to be affected by sex, age, and other, nongenetic components such as diet. We have exploited the differences in response among various inbred mouse strains to map loci contributing to the inflammatory response. Fine mapping strategies allow the refinement of sets of candidate genes, which can be identified by positional cloning. Detection of genetic variation affecting the inflammatory response in murine models provides a basis for determining whether polymorphisms in orthologous human genes correlate with particular clinical outcomes from injury. Thus, discovery of these genes could impact patient care by acting as markers of a specific predisposition in humans.