This paper introduces the rationale for the special issue and its contributions, which bridge the literature on regional development and the Triple Helix model. The concept of the Triple Helix at the sub-national, and specifically regional, level is established and examined, with special regard to regional economic development founded on innovation and research activities. The discussion on regional competitiveness lays the foundations for the exploration of contrasting environments, sectors and administrations. The authors offer a framework that captures the array of institutions, driving factors, players and powers active at the regional level. This introductory paper presents and summarizes the articles that follow, emphasizing their contribution to the literature. It shows how the various contributions exploit the Triple Helix model to analyse policy delivery at a regional level, and describes how other models and characterizations of interactions and collaborations between institutions are being associated with the Triple Helix concept, highlighting both their shortcomings and the way they enrich its application.