In order for regions today to be globally competitive, their smart specialization strategies cannot be created by an approach limited to one particular region only. The grouping of objectives emphasizes the need to create greater external dynamism by coordinating and maximizing synergies with policy initiatives, instruments and infrastructures in other regions. In this regard, trans-regional cooperation is a central aspect and a challenge of «Smart specialization», especially for neighboring regions with a cross-border dimension. EU best practice shows that cross-border Smart Specialisation Strategies (RIS3T) are singular in the practice of the cross-border RIS approach in the EU. The examples of innovative cross-border cooperation between Portugal and Spain, Germany and France, show that the main objective of this approach is to generate economic knowledge, quality employment through localised smart infrastructure and social well-being by jointly promoting strengths and common challenges. Thus, the Cross-Border - RIS3 aims to enhance the Euroregion's participation in European tenders for inter-territorial cooperation and provides a framework for launching coordinated actions and projects capable of competing with great success in attracting funding within Horizon Europe. The development of such a strategy should be agreed and coordinated on both sides of the border - innovation organisations, clusters, universities and representatives of the European Commission's Joint Research Centre Smart Specialisation team.