Differentiated disintegration is a far more persistent feature of regional integration than one might intuitively assume. Applying a historical and comparative perspective, this chapter shows that differentiated disintegration is by far not a novel process - neither in the European Community/European Union nor in other regional organizations. Still, processes of disintegration remain rare exceptions. First, this chapter provides an exploration of how theories of European/regional integration - in particular those based on functionalist epistemology - have accommodated the challenge of disintegration. Second, it demonstrates that in the aftermath of processes of disintegration in the European Community/Union as well as in other systems of regional integration, new and relatively close forms of associations have been developed following the respective departure of a member state. The chapter argues that we gain far more nuanced understandings of both differentiation and disintegration by including both historical and comparative perspectives beyond Europe and the European Union in the debate on ‘Brexit’.