In the last 40 years, Italy has seen important changes: human pressure is increasing in flat and coastal areas while internal mountainous areas are being abandoned and naturally reforested. These changes have substantial impacts on the biodiversity of the region but no conservation strategy has ever explicitly considered them, and no systematic assessment of the existing protected areas has been carried out. We used a combination of distribution models and extents of occurrence to perform a gap analysis and an irreplaceability analysis. We evaluated the effectiveness of the protected areas for the conservation of terrestrial vertebrates, and we identified regions, species, and strategies that appear to be priorities for expanding and consolidating the existing network. The existing protected areas cannot be considered fully representative, and this is especially true for Sardinia where many of the gap species are located. The Alps and the Apennines represent the strongholds of species diversity, but most of the species of conservation interest are concentrated in the Mediterranean part of the peninsula, as well as in small areas of the plains, where human pressure is higher. Biodiversity and human presence are functionally linked through traditional agriculture and pasture and the only option for conservation is that of considering human presence and activities as an integral part of the system. In a human dominated landscape, protected areas must be planned and managed in conjunction with the matrix in which they are embedded and in the context of the environmental history of the region.