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Conservation of the Mediterranean marine ecosystems is particularly challenging; high biodiversity is combined with high human population densities and a long history of resource exploitation. Residents and users of coastal areas often perceive marine conservation and manage- ment as limiting factors to economic development. Under these conditions, the creation of compre- hensive systems of marine protected areas (MPAs) can be problematic. We selected a stretch of coast in southern Italy as a representative example of a Mediterranean coastline and nearshore marine ecosystems, featuring a complex matrix of vulnerable habitats in a landscape fragmented by multiple human activities and associated stressors. Through the use of site-selection algorithms, we investi- gated how human activities constrain MPA planning. Rather than assuming that patches of the same habitat found at different locations are interchangeable, we considered the scenario of a heteroge- neous landscape of human impacts creating high variability in habitat quality. Despite widespread human influence, identification of portions of habitats to be protected from direct human disturbance as core no-take areas is still possible using the inclusion of 10 and 30% of low and high priority habi- tat, respectively, in reserves as a conservation target. Implementation of MPAs with a limited protec- tion scheme that also include several small no-take areas could represent a feasible strategy for the conservation of Mediterranean coastal marine habitats. Moreover, MPAs could be combined with coastal zoning of activities as a means of further controlling effects over broader areas and allowing for recovery of degraded areas. Site-selection algorithms are invaluable tools for conservation plan- ning. However, careful consideration of the potential constraints imposed by local human activities and future research aimed at filling existing gaps in understanding the ecology are crucial for mak- ing this approach useful in marine conservation planning.