This project addressed regional climate change effects on aquatic food webs in the Great Lakes. We sought insights by examining Lake Erie as a representative system with a high level of anthropogenic impacts, strong nutrient gradients, seasonal hypoxia, and spatial overlap of cold- and cool-water fish guilds. In Lake Erie and in large embayments throughout the Great Lakes basin, this situation is a concern for fishery managers, as climate change may exacerbate hypoxia and reduce habitat volume for some species. We examined fish community composition, fine-scale distribution, prey availability, diets, and biochemical tracers for dominant fishes from study areas with medium-high nutrient levels (mesotrophic, Fairport study area), and low nutrient levels (oligotrophic, Erie study area). This multi-year database (2011-2013) provides the ability to contrast years with wide variation in rainfall, winter ice-cover, and thermal stratification. In addition, multiple indicators of dietary and distributional responses to environmental variability will allow resource managers to select the most informative approach for addressing specific climate change questions. Our results support the incorporation of some relatively simple and cost-efficient approaches into existing agency monitoring programs to track the near-term condition status of fish and fish community composition by functional groupings. Other metrics appear better suited for understanding longer-term changes, and may take more resources to implement on an ongoing basis. Although we hypothesized that dietary overlap and similarity in selected species would be sharply different during thermal stratification and hypoxic episodes, we found little evidence of this. Instead, to our surprise, this study found that fish tended to aggregate at the edges of hypoxia, highlighting potential spatial changes in catch efficiency of the fishery. This work has had several positive impacts on a wide range of resource management and stakeholder activities, most notably in Lake Erie. The results were instrumental in the development of an interim decision rule for dealing with data collected during hypoxic events to improve stock assessment of Yellow Perch. In addition, novel findings from this study regarding spatial and temporal variability in hypoxia have aided US-Environmental Protection Agency in the development of a modified sampling protocol to more accurately quantify the central basin hypoxic zone, and this directly addressed a goal of the Great Lakes Water Quality Agreement of 2012 to reduce the extent and severity of hypoxia. Finally, the study areas developed in this project formed the basis for food web sampling in the 2014 bi-national Coordinated Science and Monitoring Initiative work in Lake Erie.