Vaccine research has experienced a quantum leap after the beginning of the genomics era. High-throughput sequencing techniques, unlimited computing resources, as well as new bioinformatic algorithms are now changing the way we perform genomic studies. Whole genome sequencing will soon become the gold standard for phylogenetic and epidemiology studies and is already shedding new light on the dynamics of bacterial evolution. We believe that deep sequencing projects, together with structural studies on vaccine candidates, will allow targeting constant epitopes and avoid vaccine failure due to antigenic variability. Systems biology, which is expected to revolutionize vaccine research and clinical studies, greatly relies on high-throughput technologies such as RNA-seq. Furthermore, genomics is a key element to develop safer vaccines, and the accuracy of deep sequencing will allow monitoring vaccine coverage after their introduction on the market.