Simple SummaryChamelea gallina is a bivalve mollusc that represents one of the most important fishery resources in the Mediterranean basin. In this species, the thickness and sturdiness of the shell valves are two important characteristics as they are decisive for protection against predators and survival of specimens rejected in the sea because caught under commercial size. The aim of this work is to investigate the ability of this species to modulate the expression of genes encoding proteins involved in shell biomineralization process in response to abiotic and biotic factors. Our findings, obtained through a multidisciplinary approach, highlighted a different shell mineralization behaviour in C. gallina clams collected in sampling sites characterized by different salinity and food availability. Moreover, this study provided the first comprehensive transcriptome from mantle, the tissue responsible for shell formation. Therefore, these results contribute to increase knowledge on this process and might help in adopting ad hoc management plans for this fishery resource.The striped venus Chamelea gallina is a bivalve mollusc that represents one of the most important fishery resources of the Adriatic Sea. In this work, we investigated for the first time the ability of this species to modulate the expression of genes encoding proteins involved in biomineralization process in response to biotic and abiotic factors. We provided the first comprehensive transcriptome from the mantle tissue of clams collected in two sampling sites located along the Italian Adriatic coast and characterized by different environmental features. Moreover, the assessment of environmental parameters, scanning electron microscopy (SEM), and X-ray diffraction (XRD) measurements on valves were conducted to better contextualize RNA sequencing (RNA-Seq) data. Functional annotation of differentially expressed genes (DEGs) and SEM observations highlighted a different shell mineralization behaviour in C. gallina clams collected from two selected sites characterized by diverse environmental parameters.