Meningococcal disease is caused by a limited range of clonal complexes of Neisseria meningitidis. The disease occurs in people who lack bactericidal antibodies to this pathogen, and therefore the patients are reliant on innate immunity or components of acquired immunity other than bactericidal antibodies. Gene variants that influence the function of innate and acquired immune response components have been associated with altered host susceptibility to meningococcal disease, and some genetic factors have also been associated with more severe disease. Identification of genetic factors associated with meningococcal disease will enhance our understanding of this rare but dangerous condition which causes death and serious morbidity in young, previously fit individuals. Genetic variations in the gene cluster encoding IL-1 and in key genes including TNF, SP-A2 and CFH have been associated with susceptibility to meningococcal disease. Understanding the mechanisms underlying genetic susceptibility to meningococcal disease will permit the development of novel therapeutic measures for the treatment of Gram-negative sepsis. To enable the discovery of new mechanisms of the disease, future research will move away from small-scale association studies and instead include analysis of large patient cohorts with accurately linked clinical and demographic information.