This chapter assesses the potential scope for post-Brexit cross-border cooperation in the socio-economic development of cities and towns in the Ireland–Northern Ireland border region, arguing that it is dependent on the fulfilment of the commitments made in the Protocol on Ireland/Northern Ireland to maintain the necessary conditions for North–South cooperation. After offering a critical overview of the current policy imperatives for cooperation between Northern Ireland and Ireland, centred on Strand 2 of the 1998 Belfast/Good Friday Agreement, and how these are impacted by the UK’s withdrawal from the European Union, the chapter focuses on the role of cooperation between border cities and towns on the island of Ireland and the extent to which this is a function of a cross-border approach to territorial development. It then highlights how the post-Brexit ability of border cities and towns on the island of Ireland to engage in successful cross-border territorial development will depend not only on the willingness of local authorities and the governments in Dublin and Belfast to engage in North–South cooperation, but also on the extent to which the government in London assumes its role in maintaining the necessary conditions for Northern Ireland to be involved in such cooperation. It concludes by offering some insights into what those conditions might involve, and the prospects for their maintenance.