This article provides new insights into the role of public universities in regional development by looking at their involvement in Research and Innovation Strategies for Smart Specialization (RIS3), a key element of the current European Cohesion Policy. In the latter, stakeholders from the triple or Quadruple Helix (public, private, research and nongovernmental sectors) jointly identify areas for research, development and innovation (RDI) investment. The analysis focuses on the region of Catalonia, which hosts a mix of higher education institutions (HEIs) with different characteristics and different relationships with local innovation stakeholders. The authors examine in-depth one of the main RIS3 funding instruments recently implemented in the region: the Research and Innovation Smart Specialization Strategy for Catalonia Communities. The Communities support the implementation of action plans for industrial research and development, jointly defined by research and private-sector stakeholders in RIS3 strategic areas. The instrument embeds the characteristics of a continuous EDP and enables exploration of the challenges and opportunities that emerge when researchers engage in strategic market-oriented RDI activities. The article highlights how HEIs are evolving and adapting to the new policy environment and concludes with policy implications.