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In the decade beginning in 1996, the National Institutes of Health (NIH) budget doubled, whereas NIH funding at the University of Louisville School of Medicine increased nearly sevenfold. The schools of nursing and dentistry, the other Health Science Center schools at Louisville, experienced comparable growth. The University of Louisville was thus one of the fastest growing research enterprises in the country during this period. While there was an infusion of state funds, the authors believe that the magnitude of the research growth depended more critically on development of an effective strategic plan with closely monitored outcomes. This process included first the identification of programs of distinction deserving of investment and then the reallocation of resources from units that were not research-intensive to those that were. The strategy focused on (1) the recruitment of endowed chairs and their teams (thus the popular name for the program “Bucks for Brains”), (2) the implementation of new promotion and tenure standards, (3) the creation of research-productivity linked salary incentives, (4) the implementation of posttenure review, and (5) an effort to improve research infrastructure, including core facilities, and physical plant. The authors describe how the investment by the Commonwealth of Kentucky was structured and how accountability to the state facilitated this growth. This description of how postsecondary education reform and the infusion of modest resources through the Research Challenge Trust Fund were leveraged into a substantial return-on-investment at Louisville could serve as a guide to schools during this time of NIH budgetary constraint.