This chapter sets the stage for a comparative assessment of the stress factors that have an impact on regionalism in Europe, Latin America, and beyond. It presents an analytical framework with which to investigate commonalities, parallel developments, and diffusion effects among regionalisms around the world. The well-studied multidimensional crisis of the European Union (EU) serves as a point of departure. The EU has struggled to respond to an accumulation of challenges, such as the euro crisis and the tense relationship between Brussels and the countries most affected by it; repeated confrontations among members about how to handle unprecedented levels of immigration; growing electoral support for nationalist parties in many member states; the threat of domestic terrorism; the Russo-Ukraine conflict in the immediate neighborhood; and the British decision to leave the EU. The EU's obvious limitations in coming to grips with recent crises have damaged its reputation as a role model for regional integration worldwide.Obviously, the specific challenges and their combination are unique to the EU. The same applies to challenges facing regional organizations in Latin America or other regions of the world. Therefore, existing studies of the crisis of regionalism have usually focused on the fate of individual regions. In contrast, the aim of this chapter is to go beyond a specific regional context and come up with an analytical framework that, while inspired by real-world cases, is sufficiently general to compare the potential impact of stress factors on regionalism in different world regions.