This Policy Brief analyses the opportunities and challenges that need to be addressed and handled with an integrated approach in order to assure a well-supported and effective transnational cooperation in the Danube macro-region. Cooperation among Danube countries has particular importance as regards to coordination of Research and Innovation (R&I) activities since they contribute significantly to competitiveness and economic growth of the macro-region and are at the same time the areas where cooperation and knowledge sharing across borders may crucially contribute to achieving best results. The purpose of this Policy Brief is to identify and examine the key issues that can contribute to the enhanced R&I cooperation in the Danube macro-region. On the other hand the report also briefly summarizes discussions among the experts at the workshop organised by DG REGIO and DG JRC in Brussels in April 2014. The report thus aims to take a stock of the state-of-the art of the current Danube cooperation activities and provide some guidance to the stakeholders on how to best enhance R&I cooperation in the Danube macro-region. The guide attempts to highlight some concrete suggestions on how to better implement governance mechanisms of transnational R&I cooperation, to revise the existing financing tools of cross-border and transnational cooperation in support of the project holders, and points out some synergies between EU funding sources that may be exploited to facilitate transnational R&I cooperation in the Danube macro-region.