This paper reviews country-level evidence about the impact of global health initiatives (GHIs), which have had profound effects on recipient country health systems in middle and low income countries. We have selected three initiatives that account for an estimated two-thirds of external funding earmarked for HIV/AIDS control in resource-poor countries: the Global Fund to Fight AIDS, TB and Malaria, the World Bank Multi-country AIDS Program (MAP) and the US President's Emergency Plan for AIDS Relief (PEPFAR). This paper draws on 31 original country-specific and cross-country articles and reports, based on country-level fieldwork conducted between 2002 and 2007. Positive effects have included a rapid scale-up in HIV/AIDS service delivery, greater stakeholder participation, and channelling of funds to non-governmental stakeholders, mainly NGOs and faith-based bodies. Negative effects include distortion of recipient countries' national policies, notably through distracting governments from coordinated efforts to strengthen health systems and re-verticalization of planning, management and monitoring and evaluation systems. Sub-national and district studies are needed to assess the degree to which GHIs are learning to align with and build the capacities of countries to respond to HIV/AIDS; whether marginalized populations access and benefit from GHI-funded programmes; and about the cost-effectiveness and long-term sustainability of the HIV and AIDS programmes funded by the GHIs. Three multi-country sets of evaluations, which will be reporting in 2009, will answer some of these questions.