Abstract Processes of clustering and initiatives to promote the creation of clusters have become an important issue in regional business development policy in recent years. The concepts can be traced back to the classical notion of industrial districts, and the embedded mechanisms and features causing superior economic performance ascribed to firms within the districts. In the last decades the concept has become increasingly popular in regional and local business development policy. This chapter provides a comparative assessment of cluster initiatives in two medium sized city regions in very different economic settings, Senderborg in the southern part of Denmark, located close to the German border, and Eau Claire in Western Wisconsin, USA, as well as identifying the impact of cluster promoting policies in these settings.