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In conservation biology, understanding the causes of endangerment is a key step to devising effective conservation strategies. We used molecular evidence (coalescent simulations of population changes from microsatellite data) and historical information (habitat and human population changes) to investigate how the most-isolated populations of giant pandas (Ailuropoda melanoleuca) in the Xiaoxiangling Mountains became highly endangered. These populations experienced a strong, recent demographic reduction (60-fold), starting approximately 250 years BP. Explosion of the human population and use of non-native crop species at the peak of the Qing Empire resulted in land-use changes, deforestation, and habitat fragmentation, which are likely to have led to the drastic reduction of the most-isolated populations of giant pandas. We predict that demographic, genetic, and environmental factors will lead to extinction of giant pandas in the Xiaoxiangling Mountains in the future if the population remains isolated. Therefore, a targeted conservation action--translocation--has been proposed and is being implemented by the Chinese goverment.