Most human diseases are substantially affected by genetic factors. It now seems clear that the pathogenesis of most diseases lies in complex interactions among the genotype, the environment, and the nature of the process that leads to cell, tissue, organ, or systemic injury. The information derived from the knowledge of the recent completion of the human genome, when combined with the sophisticated tools of molecular biology, will provide the framework for more rapid identification of the genes responsible for susceptibility to disease. Genetic approaches to complex disorders offer great potential to improve our understanding of their pathophysiology, but they also offer significant challenges. There is evidence that cellular and humoral immune responses are subject to polymorphic genetic control, which could explain the well-known diversity of clinical manifestations and outcomes in critically ill patients with the same disease. Therefore, genetic differences between people may affect the likelihood of the development of diseases. Markers of susceptibility will indicate differences in individuals or populations that affect the body's response. The underlying principle of susceptibility markers is the interindividual differences that confer sensitivity or resistance to environmentally induced diseases. This article reviews some of those susceptibility factors for critical illness and acute lung injury.