Academic health centers have faced well-documented internal and external challenges over the last decade, putting pressure on organizational leaders to develop new strategies to improve performance while simultaneously addressing employee morale, patient satisfaction, educational outcomes, and research growth. In the aftermath of a failed merger, new leaders of The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center encountered a climate of readiness for a transformational change. In a case study of this process, nine critical success factors are described that contributed to significant performance improvement: performing a campus-wide cultural assessment and acting decisively on the results; making values explicit and active in everyday decisions; aligning corporate structure and governance to unify the academic enterprise and health system; aligning the next tier of administrative structure and function; fostering collaboration and accountability—the creation of unified campus teams; articulating a succinct, highly focused, and compelling vision and strategic plan; using the tools of mission-based management to realign resources; focusing leadership recruitment on organizational fit; and “growing your own” through broad-based leadership development. Outcomes assessment data for academic, research, and clinical performance showed significant gains between 2000 and 2004. Organizational transformation as a result of the nine factors is possible in other institutional settings and can facilitate a focus on crucial quality initiatives.