A growing tide of populism in Europe and the United States, combined with other factors, threatens the solidarity upon which the global health movement is based. The highest-profile example of the turn toward populism is US president-elect Donald Trump, whose proposals would redefine US engagement in global health, development, and environmental efforts. In this challenging landscape, three influential global institutions—the United Nations, the World Health Organization, and the World Bank—are undergoing leadership transitions. This new global health leadership should prioritize global health security, including antimicrobial resistance, health system strengthening, and action on mass migration and climate change. They will need to work as a team, leveraging the World Health Organization’s technical competence and mandate to set health norms and standards, the United Nations’ political clout, and the World Bank’s economic strength. Human rights, including principles of equality, participation, and accountability, should be their foremost guide, such as holding a United Nations special session on health inequities and advancing the Framework Convention on Global Health. The need for predictable and innovative financing and high ethical standards to prevent conflicts of interest can further guide global health leaders.