After half a century of success in combating infectious diseases with vaccination and antibiotics, emerging and reemerging epidemics present a new threat to human health. Meanwhile, the rapid pace of viral and microbial genomics research, largely based on the success of genomics technologies, offers new data-generating platforms and a revolutionary knowledge base for better understanding the diseases and the associated pathogens. Systematic molecular biology studies using genomics information and technologies have helped to elucidate mechanisms of virulence and pathogenicity, whereas genomics-based medical genetic studies have been used to better understand pathogen susceptibility. This progress may lead to the development of effective and safe vaccines in the future. Here we highlight the ongoing historical transition in the field of infectious disease research and clinical practice in the new era of genomics.