In this chapter, we explore how higher education can contribute to building cross-border regional innovation systems (CBRISs) through an analysis of three examples of universities attempting to work across the Dutch-German border. Our findings show that higher education institutes can contribute to building (CB)RISs by exercising regional leadership, the construction of mutual benefits, and continually taking small steps of progress towards the creation of a (CB)RIS. Higher education institutes thereby need to mediate between two sets of national tensions and we suggest that the creation of fuzzy governance spaces may facilitate the contribution of universities to innovation in cross-border regions