Neisseria meningitidis (Nm) is frequently found in the upper respiratory tract of the human population. Despite its prevalence as a commensal organism, Nm can occasionally invade the pharyngeal mucosal epithelium causing septicemia and life-threatening disease. A number of studies have tried to identify factors that are responsible for the onset of a virulent phenotype. Despite this however, we still miss clear causative elements. Several factors have been identified to be associated to an increased susceptibility to meningococcal disease in humans. None of them, however, could unambiguously discriminate healthy carrier from infected individuals. Similarly, comparative studies of virulent and apathogenic strains failed to identify virulence factors that could explain the emergence of the pathogenic phenotype. In line with this, a recent study of within host evolution found that Nm accumulates genomic changes during the asymptomatic carriage phase and that these are likely to contribute to the shift to a pathogenic phenotype. These results suggest that the presence of virulence factors in the meningococcal genome is not a sufficient condition for developing virulent traits, but is rather the ability to promote phenotypic variation, through the stochastic assortment of the repertoire of such factors, which could explain the occasional and unpredictable onset of IMD. Here, we present a series of argumentations supporting the hypothesis that invasive meningococcal disease comes as a result of the coexistence of bacterial virulence and variability factors in a plot that can be further complicated by additional latent factors, like host pre-existing immune status and genetic predisposition.