Assessing ecological and evolutionary effects across multiple scales remains a key challenge to predicting the response of populations to environmental change. We examined populations of native interior rainbow trout (Oncorhynchus mykiss gairdneri) across a landscape-scale thermal gradient using an interdisciplinary approach. We evaluated: 1) genomic structure and genome-environment associations; 2) physiologic thermal capacity in a common garden; 3) growth and habitat quality using a bioenergetic framework; 4) current and future flow and thermal regimes by integrating climate and hydrological models; and 5) spatially explicit agent-based models (ABMs) for a subset of populations to integrate data sources across scales and evaluate fitness-based elements of adaptive capacity at the demographic-genetic interface under alternative climate, land management, and translocation scenarios. Population genomic structure across the landscape was associated with geography and thermal environmental parameters, including metrics of thermal variability. Physiological and thermal performance was associated with acclimation experience and candidate adaptive loci. Habitat surveys and drift foraging models revealed higher productivity in desert streams, but predicted warming will decrease habitat capacity, especially for larger fish. Riparian vegetation and fire management were unlikely to buffer effects of climate warming on modeled montane thermal regimes. ABM models with warming predicted trout abundance decreased (desert) or was neutral/increased (montane), that the relative importance of plasticity and genetic adaptation depends on the strength of natural selection and nature of the plastic response, and that dispersal strongly affects demo-genetic dynamics. In combination, we are evaluating the contribution of genetic and plastic traits to adaptive capacity (i.e., persistence), identifying key scale(s) and uncertainties affecting eco-evo dynamics, and evaluating the relative potential for management actions to ameliorate impacts during the synthesis phase of the program. Overall, this multi-scale and interdisciplinary approach can be applied in other systems to evaluate population responses to environmental change, including complex effects of demo-genetic feedbacks.