A pure reductionist approach can sometimes be used to solve an exceptionally complicated biologic problem, and sepsis is nothing if not complicated. A serious infection promptly leads to changes in many aspects of host physiology, including alterations in circulation, metabolism, renal, hepatic, and neuroendocrine function; all of these changes happen at once, and each influences one another. It is difficult to tease apart a problem of this sort, if only because the systems affected are so profoundly interactive. The key to understanding sepsis, insofar as we do understand it at present, was found in the use of genetic tools to study the very earliest events that take place at the interface of the pathogen and the host. The continued application of both forward and reverse genetic methods, in both mammals and insects, is steadily revealing the central biochemical events that occur during infection.