Considering stagnating regional prosperity levels and growing inter-regional disparities in many economies, this paper appeals for a renewed research agenda to deepen our understanding of regional economic development. This is done by discussing different conceptual perspectives, their empirical applications and open questions and suggestions for future research. Conventional approaches view development as an outcome of and dependent upon local economic structure. That is, high regional performance is associated with specific regional industrial and human capital mixes. We argue that to deepen our understanding of the mechanisms that drive regional economic development it is helpful to apply a relational approach that pays attention to the networks between economic actors across different spatial scales, from local to global. These generate knowledge as well as access to technologies, resources and markets, thereby catalyzing income growth. To support regional policy agendas, it is further necessary to go beyond identifying regularities that structure development and engage with differing regional pathways by conducting systematic comparative analyses of local contextual and institutional conditions.