The reform of the eurozone and the concerns surrounding a potential ‘Brexit’ has given rise to a new debate about differentiation but also disintegration in the European Union. This article provides a theoretical and analytical approach to understanding how differentiation is related to the debate on distribution of competences across various levels government. It finds that differentiation has played an important role in the EU integration process since the 1950s, even though the risk of fragmentation has always existed. Facing the benefits and costs of differentiation, the member states have developed their own practices. Three ideosyncratic groups of member states can be identified in this regard: first, a group of Anglo-Scandinavian member states which refuse centralization of the EU; a Franco-German group which considers the integration through the promotion of a ‘core Europe’; and, third, a group of central and east European member states who fear that differentiation would set their interests aside and relegate them to second-class status within the EU. Finally, Brexit is not only about the status of the UK in the EU, but casts deeper questions on how to clarify the nature of relations between the eurozone and the EU as a whole.