The Patient Protection and Affordable Care Act (ACA), both directly and indirectly, has had a demonstrable impact on academic health centers. Given the highly cross-subsidized nature of institutional funds flows, the impact of health reform is not limited to the clinical care mission but also extends to the research and education missions of these institutions. This Commentary discusses how public policy and market-based health reforms have played out relative to expectations. The authors identify six formidable challenges facing academic health centers in the post-ACA environment: finding the best mission balance; preparing for the era of no open-ended funding; developing an integrated, interprofessional vision; broadening the institutional perspective; addressing health beyond clinical care; and finding the right leadership for the times. Academic health centers will be well positioned for success if they can focus on 21st-century realities, reengineer their business models, and find transformational leaders to change institutional culture and behavior.