Environmental impacts can manifest themselves in a cumulative manner over very large spatial (watershed) and temporal (decadal) scales. In response to these challenges, scientists have been developing methods that attempt to assess the complex interactions between our environment and the current and future demands of society. This article proposes a framework for quantifying cumulative changes in water quality and quantity and demonstrates its implementation in an entire watershed, the Athabasca River Basin in Alberta, Canada. The Athabasca River Basin is an ideal watershed for this study as it has undergone significant increase in urban and industrial developments that have the potential to impact this aquatic ecosystem. This framework addresses the problems of setting a historical baseline and comparing it to the current state in a quantitative way. This framework also creates the potential for predicting future impacts by creating thresholds specific to the study area. The outcome of this framework is the identification and quantification of specific stressors (dissolved Na, chloride, and sulfate) showing significant change across the entire Athabasca River Basin, as well as the development of thresholds for these parameters. This information can be used in future assessments of proposed development and possible mitigation in the basin.