Ten years of macro-regional cooperation and the contemporary post-2020 discussions are the impetus for the authors to question the role and position of macro-regions, and to examine the potential and challenges for their future. In order to position macro-regions in the context of Cohesion policy and sectoral policies we explore the current state of play of macro-regional strategies (MRS) by analysing their implementation processes through a case study analysis, and an analysis of existing studies on the approach and added-value of MRS. This two-fold approach includes an institutional mapping of Priority Area 1a “Waterway Mobilities” of the EU Strategy for the Danube Region, as well as conclusions drawn from studies conducted by the Interact programme. The assessment of challenges and potentials positions MRS within the institutional landscape of EU Cohesion policy and sectoral policies, especially with regard to its territorial dimension. The article outlines different options for the future of MRS, which are primarily seen as tools to increase coherence between sectoral policies and regional policies and also among the different layers of the latter.