Economic and social developments have taken place at the expense of the health of the environment, both locally and on a global scale. In an attempt to better understand the large-scale effects of pollution and other stressors like climate change on the health status of Mytilus edulis, mussels were collected during the first two weeks of June 2005 at three sites (one pristine and two affected by pollution) located in each of the regions of the Canadian West Coast, the St. Lawrence estuary, the Atlantic East Coast and the northwestern coast of France, covering a total distance of some 11000km. The mussels were analyzed for morphologic integrity (condition factor), gametogenic activity (gonado-somatic and gonad maturation index, vitellogenin(Vtg)-like proteins), energy status (temperature-dependent mitochondrial electron transport activity and gonad lipid stores), defense mechanisms (glutathione S-transferase, metallothioneins, cytochrome P4503A activity and xanthine oxidoreductase-XOR), and tissue damage (lipid peroxidation-LPO and DNA strand breaks). The results showed that data from the reference sites in each region were usually not normally distributed, with discriminant factors reaching the number of regions (i.e. four), except for the biomarkers gonadal lipids, XOR and LPO in digestive gland. The integrated responses of the biomarkers revealed that biomarkers of stress were significantly more pronounced in mussels from the Seine estuary, suggesting that the impacts of pollution are more generalized in this area. Mussels from the Seine estuary and the Atlantic East Coast (Halifax Harbor) responded more strongly for Vtg-like proteins, but was not related to gonad maturation and gonado-somatic indexes, suggesting the presence of environmental estrogens. Moreover, these mussels displayed reduced DNA repair activity and increased LPO. Factorial analyses revealed that energy status, cytochrome P4503A activity and Vtg-like proteins were the most important biomarkers. Adaptation to warmer temperatures was reflected at the energy status levels, mussels from both the polluted and warmer sites displaying increased ratios of mitochondrial activity to lipid stores. Regional observations of biomarkers of energy status, gametogenesis and pollutant-related effects were influenced by nutrition, oxygen availability (eutrophication), and thermal history.