This study presents an integrated analysis of the evolution of the marine environment and the human uses in Cape Creus, a Mediterranean coastal area where intense commercial fisheries and recreational uses have coexisted over the last fifty years. The investigation synthesizes the documented impacts of human activities on the marine environment of Cap de Creus and integrates them with new data. In particular, the evolution of vulnerable, exploited species is used to evaluate the fishing impacts. The effects of area protection through the establishment of a marine reserve in the late 1990s and the potential climate change impacts are also considered. The evolution of the human uses is marked by the increasing socioeconomic importance of recreational activities (which affect species and habitats) in detriment to artisanal and red coral fisheries (which principally affect at a species level). Overall, populations of sedentary, vulnerable exploited species, hard sessile benthic invertebrates, and ecologically fragile habitats, such as seagrass meadows, the coralligenous and infralittoral algal assemblages have been the most negatively impacted by anthropogenic activities. Albeit human uses currently constitute the largest negative impact on the marine environment of Cap de Creus, climate change is emerging as a key factor that could have considerable implications for the marine environment and tourism activities. The establishment of the marine reserve appears to have had little socioeconomic impact, but there is some evidence that it had some positive biological effects on sedentary, littoral fishes. Results demonstrate that the declaration of a marine reserve alone does not guarantee the sustainability of marine resources and habitats but should be accompanied with an integrated coastal management plan.