Abstract: The Tonle Sap Lake in Cambodia, both a pars pro toto and unique “beating heart” of the dynamic lower Mekong Basin, is a principal component of the complex hydrological Mekong Delta ecology. Today, its biologically-rich floodplain, home to 1.7 million people and one of the most extended collection of fish species, is extremely vulnerable to impacts of extensive and large-scale water infrastructure construction (hydropower, irrigation, flood control and water supply). Millennia-old settlement, multi-ethnic livelihood and socio-cultural practices are threatened by an increase in deforestation and monocrop cultures, a growing population, burgeoning international investment, mass tourism and various development pressures. At the same time, the ecological vitality of the lake is endangered by increasing siltation, pollution, over-exploitation of wildlife (particularly fish and bird habitats) and the spread of non-native vegetation. Cambodia’s tumultuous history, with dramatic ruptures, had a direct effect on its foundational water system. The article will reveal the inextricable weaving of the innate dynamics of landscape — soil, vegetation, topography and water — and human domination through degrees of engineering feats and progressive territorial occupation. Settlement and productive landscapes were initially developed with various modes of traditional ecological knowledge (TEK), which is still evident in the territories of numerous floating fishing and lakeside high-stilted villages. It will then critically review the past two centuries near-irreversible break of the harmonious landscape-occupation nexus where various imposed systems over-exploited the natural richness to a point where landscape disturbances threaten the collapse of ecological systems. Finally, it hypothesizes that only a deep understanding of the interrelations of the regions complex landscape ecologies and a commitment to their rejuvenation will permit future occupation for both human and non-human species.