Lessons learned from the development, implementation, and initial 8 y of study findings from a long-term study to assess the effects of pulp and paper mill effluents on receiving waters are summarized as a conclusion to a series of articles (this issue) on study findings. The study, based on industry-defined information needs, was developed via a science-based experimental design into a long-term (>10 y) watershed-scale monitoring program that integrated in-stream population/community assessment, laboratory chronic bioassays, and fathead minnow full life-cycle assays as well as water quality and effluent quality monitoring and habitat assessment in addressing the presence of effluent effects. The 4 study streams (Codorus Creek, PA; Leaf River, MS; and the McKenzie and Willamette rivers, OR) represented both bleached and unbleached kraft mill processes and effluent concentrations that ranged from near typical for the United States (0.4%) to very high (Codorus Creek = 32%). Following 8 y of monitoring, the weight of evidence suggests an absence of biological differences at stations downstream of the mill discharges for periphyton or macroinvertebrates and, with the exception of 1 of 9 large-bodied fish and 1 of 7 small-bodied fish community structure metrics for 1 river (McKenzie), an absence of differences for fish communities. Laboratory bioassay and fathead minnow full-life cycle tests supported a substantial “margin of safety” in that, depending on the effluent, adverse responses did not occur until effluent concentrations were from 2 times to more than 150 times in-stream concentrations. The incorporation of a watershed spatial scale illustrated that each sample site tended to be unique over the 28 to 50 km monitored segments with respect to habitat and that knowledge of these variables permitted accurate evaluations of effluent effects. Similarly, the multiyear study framework provided information regarding the natural seasonal and year-to-year variability in fish communities and consequently a better understanding of how potential effluent effects signals could be expressed within this variability. The study incorporated an adaptive management strategy that provided for study design and monitoring modifications over time as a way of benefiting from practical experience and knowledge gained through time and to optimize the use of study resources. Results from this initial 8 y of monitoring, to our knowledge, represent the longest-known population/community-level assessment of the in-stream effects of pulp and paper mill effluents. Beyond the lessons learned with respect to effluent effects are those related to the design and conduct of long-term watershed-scale studies that may be of use to others in developing watershed assessment or management programs.