This chapter focuses on the challenge that comparative politics faces due to processes of de-nationalization, and discusses the notion of multi-level governance used to conceptualize political phenomena in de-nationalized contexts. The first section of the chapter explains why the principle of national sovereignty is so important to comparative politics, why this principle can no longer be assumed as given, and how developments related to the erosion of national sovereignty challenge comparative politics. The second section of the chapter introduces the notion of multi-level governance, which has been developed since the early 1990s for political analysis in strongly de-nationalized settings. It retraces the scientific history of multi-level governance, which was originally used as a descriptor of policy-making in the EU, then conceptually specified, and recently worked out as a theory of state-transformation. The third section of the chapter depicts the current research agenda of scholarship on multi-level governance, and discusses the contributions to topics and themes of comparative politics, but also identifies some blind spots – notably the analysis of power struggles – where insights from comparative politics could make a fruitful contribution.