The President's Emergency Plan for AIDS Relief (PEPFAR) has spurred unprecedented progress in saving lives from AIDS, while also improving a broad range of health outcomes by strengthening country platforms for the delivery of basic health services. Now, a new endpoint is in sight--an AIDS-free generation--together with the opportunity to change the trajectory of global health through the investments made and lessons learned in doing this work. Less than a decade ago, many experts counseled against scaling up antiretroviral treatment in the developing world. They feared that patients would be unable to adhere to their regimens, that resistant strains of the virus would evolve and prevail, and that the need to sustain daily treatment for millions of people in poor settings would overwhelm fragile health systems. Today, over 6.6 million men, women, and children are on treatment, and incidence is dropping in many of the hardest-hit countries. By adopting a targeted approach to address one of the most complex global health issues in modern history, and then taking it to scale with urgency and commitment, PEPFAR has both forged new models and challenged the conventional wisdom on what is possible. In this article, PEPFAR and its partners are examined through new and evolving models of country ownership and shared responsibility that hold promise of transforming the future landscape of global health.