Over the past 50years, a large number of development initiatives have addressed the diverse social and ecological challenges in the Sahel, often focusing on a single entry point or action, resulting in only a limited degree of success. Within the last decade, the international development discourse has evolved to incorporate resilience thinking as a way to address more complex challenges. However, concrete examples as to how to operationalize resilience thinking are lacking. The Great Green Wall for the Sahara and the Sahel Initiative (GGW), a pan-African program with a strong reforestation focus, is the latest and most ambitious of these development programs to date. The GGW represents an ideal opportunity to apply resilience thinking at a large scale, but in order to do so, it must intelligently gather and centralize pre-existing interdisciplinary knowledge, generate new knowledge, and integrate knowledge systems to appropriately navigate future uncertainties of the diverse social-ecological systems along its path. Herein, after a brief description of large-scale reforestation history in the Sahara and Sahel and the conceptual evolution of the GGW, we propose a transdisciplinary research framework with resilience thinking at its core. It includes analysis of complex social-ecological systems, their temporal and spatial cross-scale interactions, and outcomes focused on the supply of abundant, diverse, equitable, and durable ecosystem services to support livelihoods in the region. If the research areas that comprise the framework were to be properly addressed, they could conceivably guide GGW actions in a way that would contribute to desirable future pathways.