This chapter investigates the role of leaders in the process of deep socioeconomic transformation since the collapse of the state socialism, with a particular focus on the emergence of a regional innovation system in Moravia-Silesia, the largest Czech old industrial region. Methodologically, the chapter is based upon a long-lasting participative observation of socioeconomic evolution performed by both authors, as well as on interviews with key stakeholders (such as the former and current representatives of various intermediate bodies, leading academics and politicians) during the period 2018-19. First, we investigate key regional stakeholders’ perception on the extent to which city and regional leaders fulfilled their roles in terms of setting up the vision and reaching and sustaining consensus among the regional stakeholders, as well as ensuring practical steps to make their vision a reality. Second, we scrutinize variation in the practices of place leadership and examine the extent to which leaders tried to institutionalize their informal networks or exerted efforts to alter the existing institutional setup. Overall, the case of Moravia-Silesia suggests that good leaders make a substantial difference, especially under generally favourable framework conditions, when - in an ideal case - they can effectively use the opportunities offered during such enabling periods. By contrast, fighting a deep crisis requires leaders of truly exceptional calibre; such leaders were not available in the region at that time.