Biomonitoring of aquatic environment and assessment of ecosystem health play essential roles in the development of effective strategies for the protection of the environment, human health and sustainable development. Biomarkers of pollution exposure have been extensively utilized in the last few decades to monitor the health of organisms and hence assess environmental status. However, the use of single biomarkers against biotic or abiotic stressors may be limited by the lack of sensitivity and specificity. Therefore, more recently, the search for novel biomarkers has been focused on the application of OMICS methodologies. Environmental proteomics focuses on the analysis of an organism's proteome and the detection of changes in the level of individual proteins/peptides in response to environmental stressors. Proteomics can provide a more robust approach for the assessment of environmental stress and therefore exposure to pollutants. This review aims to summarize the proteomic research in bivalves, a group of sessile and filter feeding organisms that play an important function as "sentinels" of the aquatic environment. A description of the main proteomic methodologies is provided. The current knowledge in bivalves' toxicology, achieved with proteomics, is reported describing the main biochemical markers identified. A brief discussion regarding future challenges in this area of research emphasizing the development of more descriptive gene/protein databases that could support the OMICs approaches is presented.