Reform of the global health system is urgently needed in response to dramatic reductions in official development assistance for health, requiring clear decisions about system functions, delivery at all levels, and operational priorities. The previously endorsed Lusaka Agenda has been overtaken by a new reality, marked by three key issues: widespread frustration with development partners and demands for local health sovereignty and leadership, the urgent need to address and adapt to severe funding cuts, and the imperative to reform the global health and financing architecture to meet these evolving challenges.