The clinical presentation of infections by Neisseria meningitidis is highly diverse. Some patients with invasive meningococcal infections develop meningitis, while others present with sepsis or even septic shock. Three major host defence systems are activated after transepithelial passage and invasion of the bacteria into the bloodstream. These include the complement pathway, the inflammatory response by cytokines and chemokines, and the coagulation and fibrinolysis pathway. These three systems are mutually dependent. Genetic polymorphisms among components of these pathways (co)regulate the susceptibility, severity and outcome of meningococcal disease. In this paper the current knowledge of polymorphisms which are known to be associated with susceptibility to and severity of meningococcal infection is reviewed.