In a globalized urban world, cross-border metropolises represent a spatial configuration emblematic of the interplay between the space of flows and the space of places. The multiplicity of contexts and processes at work can complicate the identification of what constitutes the singularity of the concept. In order to contribute to these reflections the present article hypothesizes that the specificity of cross-border metropolises does not fundamentally stem from the form they take or the nature of the cross-border integration at work, but rather from the particular role played by national borders in their formation. Opening up borders offers new opportunities for border cities and urban border regions to reinforce their positions at the heart of global economic networks, and to affirm their autonomy as cross-border regional entities. Without minimizing the possible obstructive effects of borders, it is helpful to recognize that they might also represent a resource in the composition of cross-border metropolitan regions.