ABSTRACT. Diagnosing causal factors of change at the ecosystem level is challenging because multiple drivers often interact at various spatial and temporal scales. We employ an integrated natural and social science approach to assess potential mechanisms leading to the collapse of an estuarine social-ecological system, and recommend future paths to increased system resilience. Our case study is the collapse of the eastern oyster (Crassostrea virginica) fishery in Apalachicola Bay, Florida, USA, and the associated impacts on local resource dependent communities. The oyster fishery collapse is the most recent in a series of environmental stressors to this region, which have included hurricanes and tropical storms, drought, and the Deepwater Horizon oil spill. We found it likely that the oyster collapse was not related to contamination from the recent oil spill, but rather to factors affecting oyster recruitment and survival, which may have been mediated by both human, e.g., fishing-related habitat alteration, and environmental, e.g., increased natural mortality from predators and disease, factors. The relative impact of each of these factors is likely to increase in the future because of changing climate and increased demand for fishery, water, and petroleum resources. Successful restoration and persistence of a viable oyster fishery will depend on: (1) implementation of some minimal best management practices, e.g., extensive habitat restoration via shell addition, and some spatial closures to harvest, (2) improving environmental knowledge and promoting episodic learning through enhanced monitoring and experimental management, and (3) continued community engagement necessary to produce adaptable governance suitable to responding to future unexpected challenges.