Meningococcal disease is a life-threatening illness occurring worldwide with incidence rates varying from 1 to 1000 cases per 100,000. The causative organism, Neisseria meningitidis, is a normal commensal of humans. While strains associated with asymptomatic carriage are highly diverse, a few hyper-invasive genetic clones of the species may spread rapidly through human populations, resulting in countrywide epidemics of meningococcal meningitis. N. meningitidis fitness for spread and colonization is directly linked to the capability of the bacterium to change its genome and adapt to its environment, by means of a variety of genetic mechanisms. This review addresses some of the impacts of the evolutionary potential of N. meningitidis on the occurrence of meningococcal disease.