Within the framework of Mediterranean migration studies and as a contribution to the emerging debate on the ‘local turn’, and on multiscalar approaches of region-making from different disciplines, the main objective of this article is to analyse an empirical trend that theoretically reinforces the view that cities can shape new regional domains. This city-region interface delimits the article’s two-sided argument. On one hand, the article argues that because of the increase of trans-Mediterranean relations, cities are contributing to regional-making; and, on the other hand, that this occurs through a critical process of State disengagement from the way in which the Mediterranean is configured today. After arguing for a Braudelian view of the Mediterranean as région de villes, the article conceptualizes the category of ‘regional cities’ within current geographical and international relations literature. Drawing on three examples of external city practices (city-to-city networks, city involvement in international non-governmental organization and city bilateral diplomacy with other cities), the article empirically illustrates, as a third step, the relevant different functionalities of the city that shape region-making. Finally, the article sets this empirical and theoretical focus within current European Union and State-based geo-migration politics as a top-down region-making failure. The purpose is to highlight the dissonance between the top-down region-making blockage and the historical bottom-up construct of the Mediterranean as a region of interconnected cities. This invites us to visualize regional cities as the basic component for a paradigm shift in Mediterranean migration governance.