During the twentieth century, the introduction of vaccines changed the history of mankind, eliminating most of the childhood diseases that used to cause millions of deaths. However, where conventional vaccinology approaches failed, many new and emerging infectious diseases remain a threat to health worldwide. The advent of whole-genome sequencing and innovation in bioinformatic tools radically changed the way to design and develop new and improved vaccines, starting from the genomic information of a single bacterial or viral isolate, with a process named reverse vaccinology. As the genomic era progressed, reverse vaccinology has evolved in combination with different approaches, such as transcriptomics, metabolomics, structural genomics, proteomics, and immunomics, contributing to the design of new and universal vaccines. Furthermore, the genomic information of the host is increasingly being used to aid understanding of the human immune response to vaccines.