Although much has been learned about the implementation of HIV prevention, care, and treatment services in resource-limited settings, the broader impact of the rapid scale-up of HIV programs on fragile health systems has only recently been explored. A high-level working group identified priority research questions regarding the impact of HIV scale-up on key elements of health systems: service delivery; management; information, evidence, and strategic planning; medical products, vaccines, and technologies; health financing and payments; leadership and governance; and the behaviors of providers, consumers, and communities. Rigorous multisectoral studies are needed if HIV program expansion to the millions still needing care and treatment is to continue, and if the synergies between vertically funded HIV programs and the health systems of which they are a part are to be maximized to strengthen nations' ability to meet all their health challenges.