Through 10 years of research across multiple river basins in Africa and Asia, the Challenge Program on Water and Food analyzed water, food, and poverty issues affecting 1.5 billion people living on less than $1.25 per day. The program addressed these complex problems through basin-focused research that developed sustainable solutions for water management, agricultural intensification, and benefit sharing through stakeholder engagement. Key outcomes included identifying cropping systems and land uses for the Mekong basin that increased benefits for communities while allowing for hydropower development, and institutional and technical innovations in the Ganges basin that supported diversified and resilient agricultural systems.