The Water Framework Directive (WFD) of the European Union requires member states to attain a good ecological status for all water bodies by the year 2015. This implies that the bioecological protection endpoint itself is upfront, next to abiotic chemical quality standards, as tools to protect those endpoints. Within the requirements of the Directive, ecological status and abiotic conditions will be monitored extensively. Based on the analysis of the monitoring data, authorities are required to derive Programs of Measures (PoMs) for impacted sites. Optimization of these programs requires diagnosis, to provide site-specific or catchment-specific information on the causes of observed deviations from a good ecological status. This article shows one pilot analysis of monitoring data (Scheldt River, Belgium) compiled in the scope of the EU MODELKEY project. Ecological, ecotoxicological, and statistical models are combined to quantify local ecological impact magnitudes and to identify site-specific factors that are associated with those impacts. Results show significant ecological effects in terms of taxa loss at study sites, which are highly variable among sites, with variable combinations of environmental factors associated with those effects. The results of the diagnostic approach are discussed, which appear to be complementary to the assessment of chemical status required by the Directive. Both types of assessment are useful to assist in the derivation of optimized PoMs. In addition, it could be concluded that the acute toxic pressure parameter relates to reduced taxon abundance for more than half of the studied taxa and that this parameter relates to the fraction of taxa lost under field conditions. Finally, various lessons for the execution of monitoring programs are derived because the Scheldt (bio)monitoring data set has its weaknesses, although it can be seen as typical for current monitoring programs.