Due to its geographical features and geopolitical potential, the Adriatic-Ionian region is expected to become crucial for the European Union in reaffirming its role within the region and beyond. However, recent developments such as the Ukrainian War and divergent interests and strategies of international players (including the EU, USA, China, Turkey, and Russia) are changing and challenging territorial development, increasing regional uncertainty in the medium and long term. In 2014, the EU launched the European Union Strategy for the Adriatic Ionian Region (EUSAIR) to support and foster regional territorial cooperation. The EUSAIR is a European Union (EU) macro-region strategy that addresses territorial development from a multi-governance perspective. However, since their conceptualisation, European Union macro-regions have been relegated to the role of a high-level and intergovernmental institutional platform. Unlike the other EU macro-regions, the EUSAIR has also played a central role in harmonising national-based relations among countries participating in the strategy. Indeed, for the current programming period of 2021-2027, the EUSAIR is the only macro-strategy where participants are EU member states (Italy, Greece, Slovenia, and Croatia), candidates (Albania, Serbia, Montenegro, and North Macedonia), potential candidates (Bosnia and Herzegovina), and third-party states (San Marino). This heterogeneity makes the role of EUSAIR even more challenging and strategic for the future development of the entire Adriatic-Ionian region. This paper reflects upon several pressing questions that the Adriatic-Ionian region will face by stressing the role that the EUSAIR should have in addressing them.