Abstract This paper synthesizes the contemporary challenges for the sustainability of the social-environmental system (SES) across a geographically, environmentally, and geopolitically diverse region—the Asian Drylands Belt (ADB). This region includes 18 political entities, covering 10.3% of global land area and 30% of total global drylands. At the present time, the ADB is confronted with a unique set of environmental and socioeconomic changes including water shortage-related environmental challenges and dramatic institutional changes since the collapse of the Union of Soviet Socialist Republics. The SES of the ADB is assessed using a conceptual framework rooted in the three pillars of sustainability science: social, economic, and ecological systems. The complex dynamics are explored with biophysical, socioeconomic, institutional, and local context-dependent mechanisms with a focus on institutions and land use and land cover change (LULCC) as important drivers of SES dynamics. This paper also discusses the following five pressing, practical challenges for the sustainability of the ADB SES: (a) reduced water quantity and quality under warming, drying, and escalating extreme events, (b) continued, if not intensifying, geopolitical conflicts, (c) volatile, uncertain, and shifting socioeconomic structures, (d) globalization and cross-country influences, and (e) intensification and shifts in LULCC. To meet the varied challenges across the region, place-based, context-dependent transdisciplinary approaches are needed to focus on the human-environment interactions within and between regional landscapes with explicit consideration of specific forcings and regulatory mechanisms. Future work focused on this region should also assess the role of the following mechanisms that may moderate SES dynamics: socioeconomic regulating mechanisms, biophysical regulating mechanisms, regional and national institutional regulating mechanisms, and localized institutional regulating mechanisms.