There is a general tendency, amongst policy and certain academic circles, to assume that universities are simple strategic actors capable and willing to respond to a well-articulated set of regional demands.In reality, however, universities are extremely complex organizations that operate in highly institutionalized environments and are susceptible to regulative shifts, resource dependencies and fluctuations in student numbers. Understanding universities' contributions -and capacities to contribute -to regional development and innovation requires understanding these internal dynamics and how they interact with external environmental agents. Based on a comparative study across various national settings and regional contexts, the chapter highlights the types of tensions and volitions that universities face while attempting to fulfil their 'third mission'. Building upon the existing literature and novel empirical insights, the chapter advances a new conceptual model for opening the 'black-box' of the university-region interface and disentangling the impacts of purposive, political efforts to change universities' internal fabric and to institutionalize the regional mission..