Following a design science approach, this paper develops a framework of policy design principles for fostering technology entrepreneurship in a region. These principles are grounded in research findings and describe the factors and causal mechanisms that explain the founding and success rates of both corporate and academic spin-offs. We differentiate between principles that serve the creation of spin-offs versus those focusing on their subsequent chances of success. We provide an in-depth empirical application of this framework to spin-off policy in the regions of Eindhoven and Leuven. This application of the framework serves to assess the extent to which standing spin-off policy in both regions is (1) up-to-date, (2) comprehensive as well as (3) sufficiently robust against ‘policy fashions’. Several directions for redesigning spin-off policy follow from this assessment.