Academic health centers (AHCs) are the nation's primary resource for healthcare discovery, innovation, and training. US healthcare revenue growth has declined sharply since 2009, and is forecast to remain well below historic levels for the foreseeable future. As the cost of education and research at nearly all AHCs is heavily subsidized through large transfers from clinical care margins, our institutions face a mounting crisis. Choices centering on how to increase the cost-effectiveness of the AHC enterprise require unprecedented levels of alignment to preserve an environment that nurtures creativity. Management processes require governance models that clarify decision rights while harnessing the talents and the intellectual capital of a large, diverse enterprise to nimbly address unfamiliar organizational challenges. This paper describes key leadership tactics aimed at propelling AHCs along this journey - one that requires from all leaders a commitment to resilience, optimism, and willingness to embrace change.