Infectious diseases remain an important global threat despite the continuing invention of drugs, vaccines, and other effective interventions. Two principal factors drive this continued threat: 1) efficacious interventions are nearly always met with rapid evolutionary responses on the part of pathogens and disease-transmitting vectors, reducing their potency over time, and 2) the threat of infectious diseases is dynamic and exacerbated by the growing and increasingly connected human population, as evidenced by disruptive outbreaks, epidemics and pandemics in recent years driven by Zika, Ebola, Candida auris, antimicrobial-resistant bacteria and, of course, SARS-CoV-2. Genomics, transcriptomics, and associated scientific tools for investigating pathogens in precise detail and at tremendous scale offer new means to combat existing and emerging infectious diseases. Our GCID combines deeply experienced Management, Administrative, and Technology and Data teams, with scientists who have exceptional records in microbial genomics, to apply innovative approaches to crucial problems in infectious disease research. Our four Research Projects, devoted to viral, bacterial, fungal, and parasitic diseases, and vectors responsible for their transmission, will target high priority pathogens and pathogen-host-vector systems with a major impact on the global burden of disease. To maximize synergy between Projects, our research aims were developed with a common conceptual framework and shared approaches, and leverage working relationships that have been developed through years of close collaboration and scientific dialogue within our center and with the wider community of infectious disease research and public health officials. Using those shared concepts and approaches, supported by our Cores, our GCID will pursue three broad, long-range objectives across our four Projects: Specific Aim 1: Identify and profile novel threats and therapeutic targets. We hypothesize that selectively applying genomic methods to gather and prioritize information will accelerate counter measures against the emergence of resistance to existing therapeutics and effective responses to new disease emergencies and spillover events. Specific Aim 2: Inform clinical treatments for the benefit of patients and populations. We hypothesize that genomic and transcriptomic data will improve disease treatment by more rapidly and precisely defining the basis of resistance and virulence. Specific Aim 3: Drive precision public health surveillance and responses to disease emergence. We hypothesize that genomic analyses will improve our responses to infectious threats to support public health. Impact: We will develop innovative genomic approaches and datasets to address critical gaps in knowledge and capacity across diverse infectious diseases, and disseminate data and tools to the wider community.