The Global Fund to Fight AIDS, Tuberculosis, and Malaria, launched in 2002, grew out of the response to the HIV/AIDS epidemic, which gravely threatened eastern and southern Africa. In the face of tightened budgets, the Fund will need to continue demonstrating it is getting the best ‘bang for the buck’ in improving the health of the world’s neediest. It will need to further strengthen its transparency. And it will be pressed to effectively confront TB and malaria resistance, two tough increasing challenges. But there is reason for continued optimism. With sufficient resources, dynamic leadership, and continued support from the United States and others, the Fund will be well-positioned to continue addressing the world’s three most deadly infectious diseases.