Sepsis is a serious and growing health problem among patients admitted to intensive care units. When accompanied by organ failure, sepsis carries a 30-50% case-fatality rate. Although our understanding of burn pathophysiology has grown in recent years, we are still unable to identify accurately patients who are at increased risk for infectious complications and death. Genetic predisposition is likely to explain a portion of this variation. Understanding which genes and allelic variants contribute to disease risk would increase our ability to predict who is at increased risk and intervene accordingly, as well as identify molecular targets for novel and individualized therapies. Several obstacles exist to identification of which specific alleles and loci contribute to patient risk, including achievement of sufficient statistical power, population admixture and epistatic interaction among multiple genes and environmental factors. Although increasing sample size will resolve most, if not all, of these issues, slow patient accrual often makes this solution impractical for a single institution within a reasonable timeframe. This situation is complicated by the fact that traditional analysis methods perform poorly in the face of data sparseness. Identification of risk factors for severe sepsis and death after burn injury will likely require collaborative patient enrollment as well as development of advanced analytical methodologies. While overcoming these obstacles may prove difficult, the effort is warranted, as the ultimate benefit to patients is considerable.