Management actions intended to benefit fish in large rivers can directly or indirectly affect multiple ecosystem components. Without consideration of the effects of management on non-target ecosystem components, unintended consequences may limit management efficacy. Monitoring can help clarify the effects of management actions, including on non-target ecosystem components, but only if data are collected to characterize key ecosystem processes that could affect the outcome. Scientists from across the U.S. convened to develop a conceptual model that would help identify monitoring information needed to better understand how natural and anthropogenic factors affect large river fishes. We applied the conceptual model to case studies in four large U.S. rivers. The application of the conceptual model indicates the model is flexible and relevant to large rivers in different geographic settings and with different management challenges. By visualizing how natural and anthropogenic drivers directly or indirectly affect cascading ecosystem tiers, our model identified critical information gaps and uncertainties that, if resolved, could inform how to best meet management objectives. Despite large differences in the physical and ecological contexts of the river systems, the case studies also demonstrated substantial commonalities in the data needed to better understand how stressors affect fish in these systems. For example, in most systems information on river discharge and water temperature were needed and available. Conversely, information regarding trophic relationships and the habitat requirements of larval fishes were generally lacking. This result suggests that there is a need to better understand a set of common factors across large-river systems. We provide a stepwise procedure to facilitate the application of our conceptual model to other river systems and management goals.