Advances in genomics and innovative strategies such as reverse vaccinology have changed the concepts and approaches to vaccine candidate selection and design. Genome mining and blind selection of novel antigens provide a novel route to investigate the mechanisms that underpin pathogenesis. The resulting lists of novel candidates are revealing new aspects of pathogenesis of target organisms, which in turn drives the rational design of optimal vaccine antigens. Here we use the discovery, characterization, and exploitation of fHbp, a vaccine candidate and key virulence factor of meningococcus, as an illustrative case in point. Applying genomic approaches to study both the pathogen and host will ultimately increase our fundamental understanding of pathogen biology, mechanisms responsible for the development of protective immunity, and guide next-generation vaccine design.