The global health system is in a period of rapid transition, with an upsurge of funds and greater political recognition, a broader range of health challenges, many new actors, and the rules, norms and expectations that govern them in flux. The traditional actors on the global health stage—most notably national health ministries, the World Health Organization (WHO) and a relatively small group of national medical research agencies and foundations funding global health research—are now being joined (and sometimes challenged) by a variety of newer actors: civil society and nongovernmental organizations, private firms, and private philanthropists, and an ever-growing presence in the global health policy arena of low- and middle-income countries, such as Kenya, Mexico, Brazil, China, India, Thailand, and South Africa. We present here a series of four papers on one dimension of the global health transition: its changing institutional arrangements. We define institutional arrangements broadly to include both the actors (individuals and/or organizations) that exert influence in global health and the norms and expectations that govern the relationships among them. We focused on three central questions regarding the global health system: (1) What functions must an effective global health system accomplish? (2) What kind of institutional arrangements can better govern the growing and diverse set of actors in the system to ensure that those functions are performed? (3) What lessons can be extracted from analysis of historical experience with malaria to inform future efforts to address them and the coming wave of new health challenges?