Explosion of knowledge both in human genomics and in host inflammatory response explains the increasing interest in infectious disease genetics over the last 5 years. However, twin and adoptee studies have suggested more than 15 years ago, that host genetic factors are major determinants of susceptibility to infectious diseases in humans. Recently, candidate gene studies (association studies) and human genomewide analysis have been used to identify infectious diseases susceptibility and resistance genes. Rarely, a single gene defect has been directly related to devastating consequences such as interferon-gamma receptor mutations leading to fatal infections with ubiquitous mycobacteria. For clinical practice, gene polymorphisms of specific host immune defence elements appear to be of major importance. These genetic variants, which modify the regulation or function of the mediators, have been associated with susceptibility and/or outcome of severe sepsis and septic shock. All steps of the host response to bacteria may be affected by genetic factors. For example, Fc gamma receptor, Toll like receptor or mannose binding protein mutations have been shown to modify the detection of pathogens leading to pneumococcal severe infections, Gram-negative bacteria septic shock, and meningococcal disease, respectively. Polymorphisms of cytokine genes (TNF-alpha, TNF-beta, IL-1-ra) have been reported to influence the level of secreted mediators and to unbalance the inflammatory cascade. Coagulation response to sepsis may also be affected by gene variants such as the plaminogen activator inhibitor 1 (PAI-1) common functional polymorphism which increases the risk of death from meningococcal infection or severe trauma. The impact of these findings on the understanding of infectious disease pathogenesis and on the design of future preventive and therapeutic strategies should be considerable.