Reverse vaccinology (RV), the first application of genomic technologies in vaccine research, represented a major revolution in the process of discovering novel vaccines. By determining their entire antigenic repertoire, researchers could identify protective targets and design efficacious vaccines for pathogens where conventional approaches had failed. Bexsero, the first vaccine developed using RV, has recently received positive opinion from the European Medicines Agency. The use of RV initiated a cascade of changes that affected the entire vaccine development process, shifting the focus from the identification of a list of vaccine candidates to the definition of a set of high throughput screens to reduce the need for costly and labor intensive tests in animal models. It is now clear that a deep understanding of the epidemiology of vaccine candidates, and their regulation and role in host-pathogen interactions, must become an integral component of the screening workflow. Far from being outdated by technological advancements, RV still represents a paradigm of how high-throughput technologies and scientific insight can be integrated into biotechnology research.