Abstract 
Addressing grand challenges such as global health crises requires orchestrating diverse stakeholders across sectors and levels. While traditional orchestration focuses on decentralized, top-down coordination, less is known about “open-system orchestration,” which supports dispersed, independent efforts to tackle complex, systemic problems. This study explores how the Global Fund (GF) engages in open-system orchestration to combat HIV/AIDS, tuberculosis, and malaria. We draw on a multi-level inductive field study that spans the GF’s orchestration efforts in the headquarters (Geneva, Switzerland) and the ones at the level of local implementation in Senegal. Based on interviews, archival analysis, and observation, we identify two complementary mechanisms: political orchestration, which aligns stakeholders, manages power dynamics, and balances local autonomy, and resource orchestration, which strategically allocates resources to empower local actors. These mechanisms foster accountability, adaptability, and institutional infrastructure by creating feedback loops that connect global priorities with local needs. Our findings advance the understanding of open-system orchestration by revealing how it differs from traditional models, enabling collaborative problem-solving in contexts of global-local interplay. By demonstrating how decentralized agency and inclusive governance address grand challenges, we contribute to the literature on orchestration and cross-sector partnerships