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Recent reports highlight that the target of the United Nations and European Union of stopping biodiversity loss by 2010 will not be achieved. The halt of biodiversity loss is especially important in the Mediterranean Sea, which is considered a biodiversity hotspot for conservation priorities. The Mediterranean harbors high numbers of macroscopic marine organisms and endemic species, it has been identified as one of the largest marine areas in which the ecosystem effects of human activities are predicted to increase, and it has a complex political and geographical situation with a large number of countries with coastal areas and the two shores of the sea. Among all driving forces of biodiversity loss and related changes in ecosystem, fishing causes one of the greatest impacts. As a consequence of the main threats affecting marine ecosystem, at least 28 species of fishes, seabirds, turtles and mammals are in an endangered or critical endangered situation. The current legislation to protect and enhance the Mediterranean biodiversity and its resources still lacks the establishment of an ecosystem-based management. Following the current trend of surface increase of the Marine Protected Areas in the Mediterranean Sea, we predicted that 20% of the whole area could be protected in 2019. Nevertheless this prediction could be delayed until 2049 considering the trend of increase in the surface of No-Take Marine Protected Areas. The way forward for biodiversity conservation in the Mediterranean Sea requires an enhancement of marine spatial planning, integrating the best available information (ecological, economical and social) to make decisions and develop strategies and monitoring programmes to conserve and promote biodiversity while minimizing effects on stakeholders.