For the past 21 years, the J. Craig Venter Institute (JCVI) has applied leading edge genomics approaches to diverse problems in biology. Through significant changes in sequencing technology, an emphasis has been maintained on establishing a robust sample and data handling infrastructure and computational analysis tools to take advantage of increasingly large and complex genomic and transcriptomic datasets. The JCVI Genomic Center for Infectious Diseases (GCID) is built around a central theme - the application of innovative genomics-based approaches to study pathogens and determinants of their virulence, drug-resistance, immune-evasion, and interactions with the host and the host microbiome. The JCVI GCID will address critical issues in pathogen biology including (among others), the evolutionary dynamics of viruses in human hosts and animal reservoirs, the dissemination of antibiotic resistance in bacteria, the search for novel antifungal drug targets, and the basis for immunity to malaria infection by Plasmodium falciparum. The hypothesis-driven Research Projects will be supported by a Technology Core and a Data Management and Analysis and Resource Dissemination (DMARD) Core. An Administrative Core will assure effective management and integration of the Program components so as to take best advantage of shared approaches, samples, and insights. An outreach program will be established to promote the use of genomics in other institutions and countries. All of the data, software tools, and strain resources will rapidly be made publicly available to support the broadest use by the scientific community. The impact of the JCVI Program will prove to be very high as it addresses the basic science issues that will underpin solutions to some of the major problems and challenges in the prevention and management of infectious diseases today.