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Accelerating clinical and translational science and improving healthcare effectiveness, quality, and efficiency are top priorities for the United States. Increasingly, the success of such initiatives relies on leveraging point-of-care activities, data, and resources to generate evidence through routine practice. At present, leveraging healthcare activities to advance knowledge is challenging. Underlying these challenges are a variety of persistent technological, regulatory, fiscal, and socio-organizational realities. Fundamentally, these result from the fact that the current healthcare system is designed around a paradigm that enables individual patient care and views the connection between research and practice as unidirectional (ie, research findings are applied to practice using evidence-based medicine) but does not support research-related activities during practice. We suggest that a fundamental paradigm shift is needed to redefine the relationship between research and practice as bidirectional rather than unidirectional and propose the concept of evidence generating medicine to provide a framework for realizing such a shift. We discuss how a transition toward evidence generating medicine would result in a range of much-needed system-level changes that would facilitate rather than frustrate the ongoing efforts of informaticians, health services researchers, and others working to accelerate research and improve healthcare.