Deep sea is the largest and likely the most biologically diverse ecosystem of the world, but it is also the most unknown. The Mediterranean Sea (< 1% of the ocean surface and contains only the 0.3% of its volume) is a hot spot of marine biodiversity containing ca 7.5% of the world marine biodiversity, associated with a multitude of habitats spreading from the coast to its dark portion (e.g., coral banks, seamounts, canyons, and hydrothermal vents). Its deep-sea ecosystems are increasingly subjected to direct anthropogenic impacts (including overishing, chemical pollution, dumping, litter, and plastics), which are often over-imposed to the increasing efects of global change. Here, are illustrated the expected impacts of shifts in the main variables such as temperature, food supply, pH, and oxygen on the deep Mediterranean Sea ecosystems. One of the most consequences is related to shifts in the quality and quantity of the inputs of organic matter to the deep sealoor. The deep Mediterranean Sea is far more oligotrophic than other oceans at equal depths, and although deep-sea biota reacts to food shortage by increasing their eiciency in its use, a decrease in food availability can have dramatic efects on its food webs. The deep Mediterranean Sea is showing a clear rise of deep-water temperatures. In the last decades, deep-water warming is accelerating at unprecedented rates, causing a signiicant shift in biodiversity even for variations in the order of 0.1 °C. Higher temperatures increase deep-sea metabolism, thus exacerbating the efects of food limitation. Moreover, ocean acidiication reduces the calciication capacity of corals and alters their metabolism. Although it can be expected that increasing temperatures might increase the potential spread of oxygen minimum zone, so far, only ipoxic events were reported in Mediterranean Sea. The analysis of potential ecosystem vulnerability indicates that the ecosystems that are most sensitive to global change are deep-water coral systems and deep-sea plains. In addition, deep-sea canyons are also likely increasingly subjected to physical disturbance as a result of the increase in the frequency and intensity of climate-driven episodic events. Available information also suggests that biodiversity and ecosystem functioning of the deep Mediterranean Sea is undergoing dramatic changes, which result in accelerated organic matter biogeochemical cycling, miniaturization of the organisms' size, increased metabolism, dominance of the microbial components, and mortality rates of deep-sea biota. Given the high sensitivity of the Mediterranean Sea to global change in comparison with other oceanic regions, and the vulnerability of its deep-sea habitats/ecosystems, speciic policy measures are needed to protect its biodiversity, restore damaged habitats, and increase deep-sea ecosystems resistance and resilience to the ongoing impacts of global change. Keywords Global change • Deep Mediterranean Sea • Deep-sea biology • Ecosystem vulnerability 1 Global Change in the global oceans and trend...