Vaccines can be powerful tools, but for some diseases, safe and effective vaccines have been elusive. New developments in nucleic acid sequencing, bioinformatics, and protein modeling are facilitating the discovery of previously unknown antigens through reverse vaccinology approaches. Sequencing the complementarity- determining region of antibodies and T cell receptors allows detailed assessment of the immune repertoire and identification of paratopes shared by many individuals, supporting the selection of antigens that may be broadly protective. Systems vaccinology approaches to asses the global host response to vaccination by evaluation of differentially expressed genes in blood, cellular or tissue transcriptomes can reveal previously unknown pathways and interactions related to protective immunity. While it is important to remember that discoveries made through reverse vaccinology and systems vaccinology must still be confirmed with traditional challenge models and clinical trials, these approaches can provide new perspectives that may help solve longstanding problems in veterinary vaccinology.