Vaccines have a significant impact on public health, and vaccinology in the era of genomics is taking advantage of new technologies to tackle diseases for which vaccine development has so far been unsuccessful. Almost all existing vaccines were developed based on traditional vaccinology methods, which relied on empirical screening of a few candidates at a time, based on known features of the pathogen. However, the ability to sequence a pathogen's genome provides access to its entire antigenic repertoire. As such, genomics has catalysed a shift in vaccine development towards sequence-based 'Reverse Vaccinology' approaches, which use high-throughput in silico screening of the entire genome of a pathogen to identify genes that encode proteins with the attributes of good vaccine targets. Furthermore, the increasing availability of genome sequences has led to the development and application of additional technologies to vaccine discovery, including comparative genomics, transcriptomics, proteomics, immunomics and structural genomics. Vaccine candidates identified from a pathogen's genome or proteome can then be expressed as recombinant proteins and tested in appropriate in vitro or in vivo models to assess immunogenicity and protection. The process of reverse vaccinology has been applied to several pathogens, including serogroup B Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumoniae and pathogenic Escherichia coli, and has provided scores of new candidate antigens for preclinical and clinical investigation. As novel genome-based technologies continue to emerge, it is expected that new vaccines for unmet diseases will be within reach.