Higher Education Institutions (HEIs) and their relations to regional development have raised political expectations and scientific interest since the middle of the twentieth century. The high number of scientific surveys conducted calls for a meta-analysis that integrates multidisciplinary case study results. This secondary case survey analysis offers new insights into the scientific knowledge base on HEI-region relations. Knowledge gaps as well as uncertain, single and cross case verified knowledge could be identified. Whereas the unilateral HEIs’ impacts on the region have been broadly analyzed, there still is little knowledge on how to improve the HEIs-region relations. The article discusses the role of HEIs, which—being initially perceived as mere location factor—evolved to an active actor in the regional innovation and governance system. The article furthermore offers recommendations for policy makers and practitioners on how to use the knowledge gained for the further development of the HEI-region relations but also how to deal with knowledge gaps and context-specific research results.