The aim of this paper is to describe and analyze the effects of radical changes within regions by providing an empirical base from 12 Swedish municipalities from different regions. The specific focus of the paper is the role of entrepreneurship, both as an opportunity-seeking activity in order to find and develop new business undertakings, as well as entrepreneurship as a perspective for supporting activities in the public or private spheres. The results are based on interviews and surveys, secondary data, information from regional governments, municipal websites and also from other public information channels. Two questions were raised in analysing the case: (1) What types of contextual factors are of strategic importance when regions are challenged by radical change, and what role do these factors have in a regional restructuring and development process? (2) What types of policy and support measures are productive for entrepreneurial activities in regions when adaptation to radical change is required? The results presented by the study provide insight into how the development of local economies is affected when conditions change in a region due to the closure of a major public workplace. The paper also tries to present opportunities through which municipalities are able to prepare for and take action to help entrepreneurial activity face ongoing structural change and a globalized local economy.