A well-functioning regional innovation system involves a lot of communication and interaction among the actors. However, sometimes the communication and interaction create tensions impeding regional development. In order to explore the reasons behind this, this study looks at the relationships between key stakeholders in the Twente Region in the Netherlands. The region has an established reputation for innovation and entrepreneurship, a high inter-connectedness between the actors, and a strong knowledge infrastructure. The research focuses on the University of Twente as a key actor contributing to regional growth in close cooperation with various stakeholders. This is an introductory interview-based case study that identifies four areas of tension between the university and its regional stakeholders. Our inquiry sheds light on the misalignment of stakeholders’ interests and expectations that lessens the actors’ capacity for policy formulation and strategic agenda setting, as well as hinders its successful translation into action. Then, the absence of clear intermediaries significantly increases the perceived distance between the University of Twente and the Twente region and impedes the university’s collaboration with companies outside the science and business park. Next, the tension of discontinuity highlights the complexities of human resources and personalised networks – their diversity, multidimensionality, and overlaps make it harder to synchronise action and enhance reciprocal benefits. The knowledge asymmetry between the parties further complicates their communication and weakens commitment. In the end, the paper offers a few ideas for action for academic leaders and regional policymakers.