This paper examines the political economy of the freshwater, inland fisheries in the Mekong River basin, which are among the most productive and diverse in the world. Yet the remarkably productive fisheries of the basin, and the livelihoods of rural people this production supports, are increasingly confronting a series of threats related to hydropower development and other socio‐ecological processes. These threats are in turn driven by long‐standing efforts to transform the Mekong basin – shared by China, Myanmar, Laos, Thailand, Cambodia and Vietnam – through water resource development into a more vigorous source of regional economic development through appropriation of the basin's biophysical processes. Building on recent work on Mekong development, we highlight the biophysical and political–economic conflicts – and subsequent marginalization and devaluation of fisheries‐based livelihoods – that emerge from long‐held proposals to transform the basin into an engine of development.