The scientific community agrees on the fact that climate change and consequent impacts will not be uniform on the planet but will assume specific regional and local characteristics. Some regions of the world will therefore be more vulnerable than others. In this perspective the assessment of a system’s vulnerability must be performed at a regional or local scale. Only regionally or locally oriented studies can, in fact, provide useful information for the planning of defensive and mitigating measures. The lagoon of Venice can be considered a very vulnerable system, because of its characteristics, its artistic, cultural and natural value, and the existence of relevant impacts (erosion, loss of wetlands, temporary flooding, variation of ecological parameters, saltwater penetration, pollution and its gradual transformation into a marine bay) which already affect the system and which could be intensified by change in climatic conditions and, in particular, increase in the sea level. On the basis of the few existing studies, the present paper attempts to present an overview of the Venice lagoon’s vulnerability to climate change and sea level rise, with the conclusion that in spite of an elevated fragility of the system, a detailed vulnerability assessment has not yet been performed. The paper also attempts to identify some relevant methodological points which might constitute the basis for such a study.