Vaccines developed by conventional approaches have significantly reduced global morbidity and mortality associated with infectious diseases. However, efficacious medications are still lacking for several pathogens. With the advent of genomics, vaccine discovery has dramatically changed leading to the establishment of reverse vaccinology, which can predict vaccine candidates prior to experimental testing. Today, antigen selection can be performed through a multifold approach, based on the reverse vaccinology principles, but with the inclusion of information from multiple omics such as proteomics, transcriptomics, immunomics, and structural biology. Once vaccine candidates have been selected, systems biology can be used to interpret host responses to vaccines in clinical trials and identify correlates of protection. We believe that omics-based vaccine discovery approaches have the potential to develop efficacious vaccines against diseases lacking known protective mechanisms and for which conventional vaccinology failed.