To understand the effects of anthropogenic stressors in multi-stressor environments, managers must consider biota patterns in the context of natural environmental conditions (e.g. flow, temperature), point- and non-point discharges, and taxa-and end-point specific responses (i.e., physiological biomarkers vs. assemblage-level metrics). These assessments benefit from an integrated, weight-of-evidence framework that considers effluent toxicity, exposure relationships, and in-stream response in the context of spatial and temporal variation. Measurements made during a long-term receiving water study (LTRWS) assess effluent toxicity, and examine surface water and biota patterns relative to non-point source and inputs from tributaries and pulp and paper mill effluent discharge. Initiated in 1998, evaluations include effluent toxicity (short-term toxicity tests, fish life cycle studies), and habitat and water quality relationships to fish, macroinvertebrates, and periphyton from multiple sites (n=5-7) in four streams (Codorus Creek, PA; Leaf River, MS; McKenzie and Willamette Rivers, OR). In all streams, most measured water quality parameters were variable across seasons and years, although annual patterns were generally consistent across sites. Statistically significant increases in some parameters (e.g., COD, color, conductivity, hardness) were seen at some sites downstream of the effluent discharges relative to upstream sites, and most evident in the small, effluent-dominated Codorus Creek. In short-term toxicity tests (n>100), fathead minnow growth and Ceriodaphnia dubia reproduction was typically unaffected even in 100% effluent exposures, while fathead minnow life cycle tests examining effluent-exposed fish at key life stages showed that eggs/female/day was the most sensitive endpoint measured and that effects were not seen until 3-40x the instream effluent concentrations. Spatial and temporal patterns of fish, macroinvertebrate, and periphyton assemblages were driven by stream size, with seasonal and annual variation predominant the larger rivers (Leaf, McKenzie, Willamette), while spatial patterns were more prevalent in Codorus Creek biota. The integrated, multi-faceted study design of the LTRWS enables driver-response evaluations that inform management decisions.