Since its beginning, the European Neighbourhood Policy (ENP) has sparked debates about how the EU envisages relations with its neighbourhood. One of the most contested aspects has been the relationship between bilateralism, multilateralism and region-building, and how these different forms of political relations interact and, ideally, ensure harmonious relations between the EU and its neighbours. As this chapter shows, and the revised ENP (launched in November 2015) has confirmed, the EU has relied consistently on bilateralism, but it has also engaged with region-building in its neighbourhood. Region-building displays a different trajectory in its eastern and southern components, with the emphasis shifting from region-building to bilateralism in the South, whereas region-building has increased in relevance in the East. This chapter provides an overview of the interplay between bilateralism and region-building across time and in the shadow of power asymmetries in the area.