In this chapter, we present a combination of methodologies for investigating multiple stressor effects of effluent discharge on river ecosystems. We focus on the integration of laboratory, field, and experimental manipulation studies that help identify cause-and-effect relationships and generate weight-of-evidence ecological risk assessments for rivers. The chapter (1) outlines a basic methodology for assessing the biological responses to an effluent discharge (i.e., a point source); (2) demonstrates how nutrient diffusing substrate bioassays can be used to evaluate the effect of effluents on nutrient limitation of algal biomass; (3) illustrates the usefulness of field-based toxicity bioassays to determine contaminant effects of effluents; and (4) introduces the use of stream mesocosms as an approach to establish causality between stressors and biological effects. Together, the different methods provide a process through which key stressors are identified, ecological effects are measured, and subsequent investigations into the cause of effects are conducted.