Modern and future challenges address different levels of complexity in terms of number and diversity of variables as well as stakeholders and economic sectors. Both Marginal Seas and Oceans constitute one of the most complex socio-economic systems whose interconnections with the environment, its resources, natural and anthropogenic hazards and the increasingly growing human activities cannot be treated in isolation. This intrinsic “natural” complexity is embedded in a legislative framework resulting in a very complicated governance and management of decisions and actions. Typically, the difficulties of tackling such challenges can be approached on short and long timescales as well as on local, regional and global spatial scales. The regional approach, usually adopted to reduce the disparities towards regional development growths, shows many pros in tackling common challenges, especially when the trans-boundary aspects of possible solutions are considered as fundamental, and where diversities and commonalities have to be integrated in the strategic planning and implementation of effective actions. In this context, any solution is usually fit-to-purpose and composed by many typologies of interventions: knowledge-based support to policy is crucial to make actions effective and efficient, requiring an adaptive and flexible governance to match the spatial and timescales of the dynamics of the system. Open science can definitely help stakeholders and decision makers to make knowledge-based choices and reduce potentially conflicting uses of marine environments and ecosystem services. The Bluemed initiative can be considered an example of innovative approach to tackle the marine and maritime challenges in the Mediterranean Sea, trying to define a common pan-Mediterranean view of the key problems, to create a better awareness of this basin as a common good and to align funding schemes among Countries.