The present study assesses the resilience of the Mediterranean gilthead seabream (Sparus aurata) to acute warming and water acidification, using cellular indicators of systemic to molecular responses to various temperatures and CO2 concentrations. Tissue metabolic capacity derived from enzyme measurements, citrate synthase, 3-hydroxyacyl CoA dehydrogenase (HOAD), as well as lactate dehydrogenase. Cellular stress and signaling responses were identified from expression patterns of Hsp70 and Hsp90, the phosphorylation of p38 MAPK, JNKs and ERKs, from protein ubiquitylation and finally from the levels of transcription factor Hif-1α as an indicator of systemic hypoxemia. Exposure to elevated CO2 levels at temperatures higher than 24 °C generally caused an increase in fish mortality above the rate caused by warming alone, indicating effects of the two factors and a failure of acclimation and thus the limits of phenotypic plasticity to be reached. As a potential reason, tissue-dependent induction and stabilization of Hif-1α indicate hypoxemic conditions. Their exacerbation by enhanced CO2 levels is linked to the persistent expression of Hsp70 and Hsp90, oxidative stress and activation of MAPK and ubiquitin pathways. Antioxidant defence is enhanced by expression of catalase and glutathione reductase, however, leaving superoxide dismutase suppressed by elevated CO2 levels. On longer timescales in specimens surviving warming and CO2 exposures, various metabolic adjustments initiate a preference to oxidize lipid via HOAD for energy supply. These processes indicate significant acclimation up to a limit and a time-limited capacity to survive extreme conditions passively by exploiting mechanisms of cellular resilience.