The present paper straddles the systems of innovation and the economic geography theories which conceptualize universities as engine of regional development and drivers of growth. These approaches, we argue, overlook the heterogeneity of universities in the process of engagement and assume their equal capacity to contribute to their innovation policy space. In the view proposed here the university does not only influence the surrounding region, but also region is shaper of university performance. The paper puts in perspective differences between university profiles in Spain based on their strategies and performance and the scale and scope of the capabilities to contribute to their regions. In addition we analyze differences between university clusters to fulfill the missions of teaching, research and social engagement as the main strategies of HEIs.