Biomedical science is at an evolutionary turning point. Many of the rate-limiting steps to realizing the next generation of personalized, highly targeted diagnostics and therapeutics rest at the interstices between biomedical science and the classic, university-based disciplines, such as physics, mathematics, computational science, engineering, social sciences, business, and law. Institutes, centers, or other entities created to foster interdisciplinary science are rapidly forming to tackle these formidable challenges, but they are plagued with substantive barriers, born of traditions, processes, and culture, which impede scientific progress and endanger success. Without a more seamless interdisciplinary framework, academic health centers will struggle to move transformative advances in technology into the foundation of biomedical science, and the equally challenging advancement of models that effectively integrate new molecular diagnostics and therapies into the business and social fabric of our population will be similarly hampered. At the same time, excess attention on rankings tied to competition for National Institutes of Health and other federal funds adversely encourages academic medical centers (AMCs) and universities to hoard, rather than share, resources effectively and efficiently. To fully realize their discovery potential, AMCs must consider a substantive realignment relative to one another, as well as with their associated universities, as the academy looks toward innovative approaches to provide a more supportive foundation for the emergent biomedical research enterprise. The authors discuss potential models that could serve to lower barriers to interdisciplinary science, promoting a new synergy between AMCs and their parent universities.