Since the end of the Second World War, the United States has developed the world's preeminent system for biomedical research, one that has given rise to revolutionary medical advances as well as a dynamic and innovative business sector generating high-quality jobs and powering economic output and exports for the U.S. economy. However, there is a growing concern that the biomedical research enterprise is beset by several core challenges that undercut its vitality, promise, and productivity and that could diminish its critical role in the nation's health and innovation in the biomedical industry. Among the most salient of these challenges is the gulf between the burgeoning number of scientists qualified to participate in this system as academic researchers and the elusive opportunities to establish long-term research careers in academia. The patchwork of measures to address the challenges facing young scientists that has emerged over the years has allowed the U.S. biomedical enterprise to continue to make significant scientific and medical advances. These measures, however, have not resolved the structural vulnerabilities in the system, and in some cases come at a great opportunity cost for young scientists. These unresolved issues could diminish the nation's ability to recruit the best minds from all sectors of the U.S. population to careers in biomedical research and raise concerns about a system that may favor increasingly conservative research proposals over high-risk, innovative ideas. evaluates the factors that influence transitions into independent research careers in the biomedical and behavioral sciences and offers recommendations to improve those transitions. These recommendations chart a path to a biomedical research enterprise that is competitive, rigorous, fair, dynamic, and can attract the best minds from across the country.