This supplement introduces the African Health Initiative (AHI), a research program comprised of five unique district health system-strengthening activities in Ghana, Mozambique, Rwanda, Tanzania, and Zambia that began in 2009 (Figure (Figure1).1). This supplement should be of interest to all engaged in improving delivery of district primary health care — whether ministries of health, service providers, funders, or those who evaluate complex interventions. The five AHI projects, known as Population Health Implementation and Training (PHIT) Partnerships, are funded by the Doris Duke Charitable Foundation (DDCF) with a common goal: to produce significant, measureable health improvements in a defined geographic area over a five to seven year grant period. With the partnerships in their fourth year of funding, it is now possible to capture lessons learned in project design and implementation. Evaluation of the African Health Initiative’s impact on population health, including mortality, however, must await the conclusion of the grant period. Figure 1 Population health implementation and training partnership sites Why focus on health systems? The last two decades saw unprecedented growth in the level of assistance available for health in developing countries. Although health expenditure by African governments remains below the Abuja Declaration target (15% of government expenditure) [1], donor support for health more than tripled between 1990 and 2008 [2] , reaching more than $27 billion annual expenditure in 2010 [3]. Much of this support is directed at “big diseases”, notably HIV/AIDS, tuberculosis, and malaria, often under the auspices of new global health initiatives. These laudable, ambitious efforts to target major killers encountered already fragile, under-resourced health systems that limited the capacity of beneficiary countries to absorb new investments. Although there are no simple, fast solutions to strengthening health systems, the World Health Organization [4] and others, notably the Alliance for Health Policy and Systems Research, have been central in promoting a dialogue on how to address this critical issue [5]. In 2006, as global health funding was increasing, the Doris Duke Charitable Foundation Board of Trustees was considering one or two new initiatives, spurred by a desire both to celebrate its upcoming 10th anniversary of grant making and a surge in returns on its endowment. The Foundation’s Medical Research Program supported mainly domestic clinical research. Only a small portion of DDCF’s grant making was directed to research on the treatment and care of AIDS patients in Africa and the construction of the Doris Duke Medical Research Institute in Durban, South Africa. It was these latter activities that brought DDCF staff to several sub-Saharan African countries. On an early visit, staff were struck by the presence of a new HIV clinic — stocked with needed medicines and supplies and staffed by a proud health worker –- while across the street was a district hospital —derelict, no supplies, crumbling infrastructure, few staff, and patients lying on the ground for lack of beds. Further visits confirmed that, as AIDS treatment rolled out, such contrasts were common throughout sub-Saharan Africa. How could it possibly make sense for a woman to attend this new HIV clinic, and then have to contend with a non-functioning community clinic and an under-resourced district hospital for pregnancy care, childhood immunizations, or management of malaria? Not only did it seem logical that health clinics should provide integrated primary care for an entire family, but also that those clinics be part of a health system that could deliver drugs and supplies on time, train workers, and, when required, refer patients for treatment of complicated cases. Although how to define, assess, and measure health systems continues to pose challenges [6], it was these real-world observations, consultation with a range of experts, and the belief that the Foundation should be willing to address critical gaps even if they were ‘hard and high risk,’ that propelled DDCF to invest in health systems strengthening. Staff were heartened by findings of the Tanzanian Essential Health Interventions Project (TEHIP) [7] and the Navrongo Experiment in northern Ghana [8], both of which suggested that health systems interventions could indeed result in meaningful population health gains in a relatively short period of time.