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The U.S. biomedical research enterprise has played a vital role in advancing science, human health, and the economy. It has contributed significantly to fields such as agriculture, environmental remediation, job creation, and technological innovation. Over the past 80 years, landmark achievements include reducing cancer mortality, developing HIV/AIDS treatments, sequencing the human genome, and creating vaccines that mitigated the impact of the COVID-19 pandemic. The enterprise has grown remarkably in less than a century and holds even greater potential for future success. However, its progress is hindered by a lack of high-level national coordination, a fragmented funding system, and a declining workforce.The State of the U.S. Biomedical and Health Research Enterprise: Strategies for Achieving a Healthier America addresses these challenges in five key areasstrategic vision, funding, health equity, coordination and convergence science, and workforce developmentoffering a roadmap that could be used to sustain U.S. leadership in global health.