Globalization is having a growing impact on health and health care, presenting challenges as well as opportunities for the U.S. health care industry in general and for academic health science systems (AHSSs) in particular. The authors believe that AHSSs must develop long-term strategies that address their future role in global medicine. AHSSs should meet global challenges through planning, engagement, and innovation that combine traditional academic activities with entrepreneurial approaches to health care delivery, research, and education, including international public-private partnerships. The opportunities for U.S.-based AHSSs to be global health care leaders and establish partnerships that improve health locally and globally more than offset the potential financial, organizational, politico-legal, and reputational risks that exist in the global health care arena. By examining recent international activities of leading AHSSs, the authors review the risks and the critical factors for success and discuss external policy shifts in workforce development and accreditation that would further support the growth of global medicine.