Abstract The fate of regions and industries are often intertwined. When industries thrive, regions and their constituents benefit. However, when industries decline, regions often require new paradigms to replace the old paradigms, and infuse new economic life into the region. This study enhances understanding of the regional characteristics that hinder or promote creative destruction. It enlightens the field on the geographic origins of creative destruction by theorizing about a region's structural (determined by industry clustering and regional knowledge), social demography and political economy attributes, and their influence on the region's capacity to incubate creative destruction.