We analyzed the technical basis for a major global program to reduce disease among the poor. Effective interventions exist against the few diseases which most account for excess mortality among the poor. Achieving high coverage of effective interventions requires a well-functioning health system, as well as overcoming a set of financial and nonfinancial constraints. The annual incremental cost would be between $40 billion and $52 billion by 2015 in 83 low-income and sub-Saharan African countries. Such a program is feasible and would avoid millions of child, maternal, and adult deaths annually in poor countries.