Biological effects techniques have been used with the aim to further integrate biological effects measurements with chemical analysis and apply these methods to provide an assessment of mussel health status. Live native mussels were collected from selected coastal and estuarine sites around the British Isles, including the rivers Test, Thames, Tees, and Clyde, and Lunderston Bay. A suite of biological effects techniques was undertaken on these mussels, including whole organism responses (scope for growth), tissue responses (histopathology), and subcellular responses (lysosomal stability, multi-xenobiotic resistance [MXR], and Comet assay). In addition, whole mussel homogenates were used to measure organic (polycyclic aromatic hydrocarbons [PAH], polychlorinated biphenyls [PCB]) and metal concentrations. Overall the mussels collected from the Thames were in relatively poor health, based on histopathological markers, significantly higher DNA damage, and elevated expression of MXR detoxifying proteins. In contrast, the mussels collected from the River Test were in the best health, based on histopathological markers, respiration rate (SFG), and low frequency of DNA damage. In conclusion, the biological effects techniques were able to distinguish between relatively contaminated and clean environments, with the Thames mussels in worst health. Mussel tissue chemistry data were not able to explain the variations in biological response. Evidence indicates that the difference in the health of the mussels between the different sites was due to either effects of contaminants that were not measured, or the combined effects of mixture toxicity resulting in a threshold effect.