In the framework of the European Commission Blue Growth Strategy, a joint process among European countries has been put in place since 2014 to promote and implement research and innovation actions to increase the number of jobs in the marine and maritime sectors, commonly named ‘blue’, and pursue a sustainable growth in the Mediterranean area. The process has then been extended to the non-European (non-EU) Mediterranean countries. The natural and cultural uniqueness of the Mediterranean Sea is recognized worldwide, and the opportunities for social and economic growth in the area are increasing. At the same time, natural and anthropogenic pressures as well as the need for a governance of common space and resources add complexity to the management of such area, whose countries belonging to three different continents have socio-economic differences and express a variety of cultures and political regimes. This paper provides insights on the steps that brought to the development of the BLUEMED Initiative and the progresses made from its launch and the publication of the BLUEMED Strategic Research and Innovation Agenda (SRIA) by European Mediterranean countries to its extension in non-EUones. It highlights key activities carried out at a policy level and focuses on the tools used for engaging all relevant stakeholders, namely scientists, policy makers, private companies, and civil society, at national and international levels. Moreover, it reports recent activities towards a structured involvement of non-EU countries. Preliminary outcomes of the process indicate that the scientific approach is crucial to manage complexity, not only as a vehicle of diplomacy but also to support knowledge-based decisions.