The Tonle Sap water-related crisis mainly concerns governance, and at both the local and cross-boundary levels the crisis requires a more integrated and comprehensive solution than is the case at present. This paper addresses the institutional challenges of this basin from three levels: international collaborative facilitation and resource mobilization toward sustainable development of the Mekong region, national and local institutional matters, and participatory issues. The results show that new governance principles such as a holistic institutional approach and upstream–downstream relationship, transparency and accountability, public participation and decentralization, gender and equity, and separation of incompatible administrative functions, etc., are much needed in the Mekong and Tonle Sap Basins. The governance should have a greater emphasis on broader policy and planning, and more strategic approaches and attention to equity, sustainability and poverty alleviation.