There is no doubt that, in infectious disease, genetic predisposition plays a very important role in clinical outcome. Sepsis is a polygenic syndrome initiated by infection. A fact confounding the situation is that two factors--the macroorganism and the microorganism--are at play at the same time; hence of genotype effect must be assessed in light of their interaction. From a phylogenetic point of view, infectious disease is a companion of man throughout their life and its role in terms of function of the system of innate immunity is perceived as a beneficial one. However, the presence of a major antigen load by the infectious agent results in pathological responses at the levels of the macroorganism. Assessment of the severity of the inflammatory process on the basis of genetic predisposition is a most challenging issue. Genetic polymorphisms in the immune response to infection have been shown to be associated with clinical outcomes. The advancement of single nucleotide polymorphism (SNP) genotyping in basic genes--CD14, Toll like receptors, LBP, cytokines, cytokine receptors and coagulation factors have provided valuable information on the interaction of the macro and microorganisms. The understanding of the variation in genes and differences in response to infection may contribute to tailored diagnostic and therapeutic interventions with improved outcome in these patients.