Water, energy, and food systems and the health of ecosystems are increasingly stressed, with the most negative impacts for poor people. These systems are inextricably linked, yet most efforts to improve water, energy, and food security and ecosystem health continue to focus on single-sector approaches that neglect the complexity of their interactions, often worsening rather than solving underlying problems. The CGIAR Initiative on NEXUS Gains uses a systems approach to better understand interlinkages and to promote interventions to boost sustainable water resource management, protect biodiversity, and provide clean and inclusive access to energy for our agri-food systems.