PROJECT SUMMARY Over the past decade, the CTSAs have made incredible progress in developing informatics tools and services to support institutional or hub-centric translational research. However, robust collaboration between the hubs is required to realize the full potential of the CTSA network, a living ecosystem of collaboration and sharing. We have brought together pioneers of open science, clinical and biomedical informatics, health science libraries, and the NCATS Translator initiative to propose the creation of a National Center for Digital Health Innovation to coalesce the CTSA informatics community together with the open science community to catalyze the next steps in the evolution of biomedical informatics. We will create an open governance model that includes all who would like to participate and collaboratively forge the next steps. We will embrace an ‘idea to implementation’ model (I2I), supporting the creation of collaboratively developed sustainable infrastructure. We will do this via the axes of open data, open software, open resources, and through two integrated thematic areas of urgent need: rare disease and human health across the lifespan. Underpinning these efforts are innovative models for evaluation, training, and the creation of community challenges as mechanisms to stimulate new and impactful tools and methods. We will leverage the power of an open and team science approach to demonstrate new research opportunities. Our leadership include Oregon Health Sciences University, Johns Hopkins University, the University of Washington, Washington University in St. Louis, Northwestern University, Sage BioNetworks, the Jackson Laboratory and the Scripps Research Institute. We have collaborators from all areas of translational informatics including health record vendors, clinical research networks and leaders in open software and open data. Together our efforts will catalyze the next stage in the evolution of the national informatics infrastructure for clinical and translational research.