A comprehensive evaluation of the results of many recent and ongoing studies has been performed in an attempt to assess which stressors are acting and what alterations could be derived for the aquatic organisms of the river Po downstream from one of its tributaries, the river Lambro. With this aim in view, this stretch of the river Po was compared with the immediate upper reach which is characterized by an overall good quality. The comparison was based on four categories of indicators, that is, watershed stress, physical-habitat alteration, and in particular chemical exposure and biological responses both of which were thoroughly examined. The reach located downstream of the river Lambro was found to be contaminated by a complex mixture of pollutants that were detected at low/moderate concentration values. This makes the area representative of what can be considered as a ‘grey’ level of pollution, that is the most frequent condition of watercourses worldwide. Nevertheless, the effects derived from such moderate/low levels of contamination for aquatic life are difficult to assess. Most of the indicators were found to be changed downstream of the river Lambro and different kinds of alterations were observed in both resident species and laboratory-test organisms. Although more information is necessary to understand less evident impairments as, for example, of the fish community, it can be concluded that a continuous interaction between chronic toxicity and trophic enrichment is the process that characterizes this riverine environment and affects the community. On the grounds of these findings, some suggestions are also proposed pertaining to ‘grey’ areas and their investigation.