"Human and veterinary pharmaceutical drugs are more and more consumed worldwide. Their detection in the environment and their bioactivity has now raised concern for potential adverse effects on non-target species. Notwithstanding recent attention for their environmental presence, there are significant research gaps for existing pharmaceuticals with regard to their potential ecological consequences. In this study, the four most abundantly used pharmaceuticals: Acetaminophen, Carbamazepine, Trimethoprim y Atenolol, will be examined for their long term effect on the genomic and proteomic expression of the gilthead seabream, Sparus aurata. These endpoints provide useful information on the xenobiotic-induced impairment resulting in the activation and silencing of specific genes by elucidating the underlying molecular mechanisms of higher level damage. Gene expression and protein products will be evaluated in liver and brain as target tissues by microarray and 2D differential gel electrophoresis (2D DIGE) techniques, and significantly up and down regulated proteins will be identified by liquid chromatography–tandem mass spectrometry (LC–MS–MS). These responses will be compared with the histopathological effects observed by histomorphological and histochemical techniques to link the toxic responses at different organizational levels. Together with already available toxicity data for this species and the chosen pharmaceutical compounds, we aim to elucidate toxicity mechanisms at molecular level that are linked with effects at higher organizational level. This will help to improve extrapolation techniques from laboratory tests to derive potential ecosystem effects. Also, the knowledge of molecular pathways and proteins involved in toxic processes forms the base for the development of specific biomarkers which will supply decision makers with information for the further monitoring of the effects of pharmaceuticals in the environment and the regulation of these compounds."