Fast-paced watershed change, driven by anthropogenic development, is threatening the sustainability of freshwater resources across the globe. Developments within watersheds interact in a manner that is additive and synergistic over space and time. Such cumulative environmental effects are defined as the results of actions that are individually minor but collectively significant when added to other past, present, and reasonably foreseeable future actions. Cumulative effects assessment (CEA) then is broadly defined as the process of evaluating the potential impacts of such collective actions on the environment and is a requirement in many countries, including in Canada at the federal level under the Canadian Environmental Assessment Act. However, current approaches to CEA for river systems are proving to be ineffective, which is largely attributed to the disconnect between CEA science and practice. We highlight this gap herein by discussing contradictions in the CEA literature, challenges in quantifying cumulative interactions, including overcoming spatiotemporal scale issues, multiple hydrologic and ecological pathways, and lack of predictive analysis. Our analysis shows there is a need for improved CEA for river systems, and in responding to this need we propose a conceptual framework for better integrating science and practice for improved CEA for river systems using one of the most adversely affected rivers basins in Canada, the Athabasca River, as our model. We conclude by addressing the challenges inherent to CEA with the intent of providing scientists with ways to help improve CEA of river systems.