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Agricultural and food systems in the Mekong Region are undergoing transformations because of increasing engagement in international trade, alongside economic growth, dietary change and urbanisation. Food systems approaches are often used to understand these kinds of transformation processes, with particular strengths in linking social, economic and environmental dimensions of food at multiple scales. We argue that while the food systems approach strives to provide a comprehensive understanding of food production, consumption and environmental drivers, it is less well equipped to shed light on the role of actors, knowledge and power in transformation processes and on the divergent impacts and outcomes of these processes for different actors. We suggest that an approach that uses food systems as heuristics but complements it with attention to actors, knowledge and power improves our understanding of transformations such as those underway in the Mekong Region. The key transformations in the region include the emergence of regional food markets and vertically integrated supply chains that control increasing share of the market, increase in contract farming particularly in the peripheries of the region, replacement of crops cultivated for human consumption with corn grown for animal feed. These transformations are increasingly marginalising small-scale farmers, while at the same time, many other farmers increasingly pursue non-agricultural livelihoods. Food consumption is also changing, with integrated supply chains controlling substantial part of the mass market. Our analysis highlights that theoretical innovations grounded in political economy, agrarian change, development studies and rural livelihoods can help to increase theoretical depth of inquiries to accommodate the increasingly global dimensions of food. As a result, we map out a future research agenda to unpack the dynamic food system interactions and to unveil the social, economic and environmental impacts of these rapid transformations. We identify policy and managerial implications coupled with sustainable pathways for change.