From 2019 to 2024, the University of Cologne has been receiving considerable state funding for establishing a Gateway Excellence Start-up Centre. A key approach is establishing nine new professorships. Seven of them are “start-up-oriented”, meaning that they deal with business foundation in their teaching, research, and student support activities, while focusing on a different academic subject. These professors are in the Faculty of Management, Economics and Social Sciences, in the Faculty of Mathematics and Natural Sciences as well as in the Faculty of Humanities and the Faculty of Medicine. The objective is to anchor entrepreneurship and innovation, also combined with digitisation, across the University. The professorships’ key task is to motivate students to think and act entrepreneurially. The University recommends to other universities that also seek to establish start-up-oriented professorships finding an approach that suits the university’s profile and framework conditions. Moreover, the university’s whole hierarchy must support the approach. Establishing such professorships is very challenging but also rewarding, as they provide new perspectives on start-ups.