Metrics characterizing the benthic macroinvertebrate assemblages in wadeable streams in the Mid-Atlantic region of the United States were analyzed to explore the relative responses of the metrics to different types of anthropogenic stress. The data used in our study were collected by the US Environmental Protection Agency Environmental Monitoring and Assessment Program from 1993 to 1996. Regression models were developed relating metric values at reference sites to natural sources of variability. These models were then used to predict reference values at test sites. Test site metric observations were scaled by subtracting the predicted reference value and dividing by the standard deviation of residuals at reference sites. Stressor–response relationships for each scaled metric were then estimated using generalized additive models. Metric responses to 4 groups of stressors (nutrient enrichment, habitat degradation, elevated metals concentrations, and elevated ion concentrations) were different. The proportional abundance of tolerant taxa was the most sensitive indicator of nutrient enrichment and habitat degradation, whereas Ephemeroptera richness was the most sensitive indicator of elevated metals or ion concentrations.