Stream ecosystems may suffer from the effects of multiple stressors. Planning restoration actions without knowing the relative weight of each stressor might lead to disproportionately costly or ecologically meaningless measures. This is particularly relevant under the EU Water Framework Directive where economic considerations play a role in justifying exemptions from the overarching aim of the directive of achieving the good ecological status in all the EU water bodies by 2015. In this study, we correlated the status of macroinvertebrate assemblages with many environmental variables at 120 monitoring stations (surveyed in 2009–2011) in the streams of Lombardy, Italy. We used a combination of regression techniques to disentangle the effects of the different stressors. Furthermore, different profiles of ecological quality were associated with the dominant stressors. Finally, examples are given about how these study findings provide elements to identify restoration scenarios that maximize the effectiveness/cost ratio.