There is increasing interest in the question of how different stakeholders develop, implement and lead regional upgrading processes with the concept of place leadership emerging as one response to this. Simultaneously, universities face growing expectations that they will contribute to regional development processes - often through their collaborative relationships with other regional stakeholders. But universities are complex in terms of their internal and institutional structures, which undermines their capacities to enact coherent place leadership roles. We seek to understand how strategic leadership in universities can contribute to innovation and regional development in the context of the fundamental institutional complexity of universities. We address this through a qualitative, explorative case study comparing six European regions where universities have sincerely attempted to deliver place leadership roles. We identify that the elements of agency and alignment are vital in that: firstly, university leadership has to align with regional coalitions on the one hand and internal structures on the other hand, and secondly, this leadership must give give individuals agency in their regional engagement activities.