Vaccination is one of the safest and most cost-effective public health interventions, which save millions of lives annually. Thanks to all the genius pioneers of the field, we have already developed many effective vaccines. On the other hand, there are still many pathogens for which we do not yet have an effective or optimal vaccine, including malaria, HIV, and tuberculosis. In the 21(st) century, biological sciences are at the edge of a growing and fruitful genomics era, which provide many opportunities for vaccine research to have a better understanding of host-pathogen interactions, immune responses, targets and thus allow the scientists to design better vaccines. After the publication of the first bacterial genome of a pathogen, Haemophilus influenza, genomics technology revolutionized the field and created novel vaccine discovery approaches like reverse vaccinology, antigenome technology, surfome analysis, immunoproteomics, and genetics vaccinology to discover novel immunogenic antigens. This review is an attempt to briefly explain these methodologies and the history of their development since the beginning of the century.