The Mediterranean Sea has been recently described as one of the most affected areas by marine litter, including microplastics, in the world. Recent studies in the different regions of the basin suggested that some areas are affected by important concentration of microplastics and plastic additives, representing a potential risk for endangered species (baleen whales, filter feeders’ sharks and sea turtles) and for the all Mediterranean biodiversity. To cover the current knowledge gaps on this issue a harmonised methodological approach for the assessment of the marine debris impact on Mediterranean biodiversity is needed. The quantification of marine litter, and particularly microplastics, in the marine environment can depend on several environmental factors and change according to multiple oceanographic features, and therefore, cannot reflect the potential impact on organisms and ecosystems. The information obtained by biondicator species could better integrate the spatial and temporal presence of marine litter/ microplastics in the marine environment. In addition, the use of biondicators can allow to measure not only the occurrence of marine litter in the species and its environment but also the threat posed to organisms by the evaluation of contaminants accumulation and any related biological effect. To assess the harm by marine litter ingestion a threefold approach, simultaneously measuring the presence and effects (accumulation of plastic associated contaminants and biomarker responses), can provide the harm and the sub-lethal effects to organisms related marine litter impact. The gaps pointed out by this research and the bioindicators species selected could represent a step forward for the risk assessment and the implementation of future mitigation measure for the Mediterranean area, habitat and species affected by marine litter ingestion. The identification of the most representative bioindicator species for marine litter/ microplastics in the Mediterranean environment is one of the main goals of the multidisciplinary strategy developed in the Plastic Busters SDSN-MED, the Union for the Mediterranean project (UfM) (http://plasticbusters.unisi.it/).