Brexit has contributed to increased discussion of a second independence referendum in Scotland, so-called IndyRef2. A successful Yes vote would require negotiations between Scotland and the rest of the UK to settle distributional questions and coordinate on cross-border policies, but there are few precedents for this and little scholarly discussion as a result. This article argues that the lessons from Brexit can help us understand what negotiating secession might look like, insofar as British withdrawal from the European Union illustrates the specific dynamics associated with exiting a pluri-national and institutionally dense union under conditions of asymmetric interdependence. Drawing on recent research on the politics of exit, this article suggests the period following a successful independence referendum will be characterised by efforts to reinterpret the referendum mandate, political change within and between parties and institutions, altered preferences in London, and a highly asymmetric bargaining environment. Understanding the lessons of Brexit can aid our understanding of the dynamics of independence and help policymakers prepare in advance for the eventuality of a Yes vote.