Abstract: What are the implications of Brexit for the nature, role, and potential of Franco-German leadership in the EU? Brexit, we contend, is both an expression and a further cause of two broader underlying developments in the contemporary EU: First, a stronger and more prominent German part and position, and second, disintegrative tendencies in several EU policy fields and the EU polity as a whole. This, in turn, has major implications for Franco-German bilateralism and for Franco-German leadership in the EU. In light of a stronger Germany, a relatively weaker France, and significant centrifugal forces, the two largest EU member states must not only realign their bilateral relationship but must also act as a stabilizer in and for the EU. We show that during the EU’s recent crises, not least during the Brexit negotiations and the recovery from the Covid-19 pandemic, France and Germany did exercise joint leadership. We also show, however, that major discrepancies persist between the two countries in particular policy fields and with regard to longer-term European objectives. Brexit, with its numerous calamities and implications, thus once again moves Franco-German leadership—and its shortcomings—to center stage in Europe. When it comes to leadership in the EU, there remains no viable alternative to the Franco-German duo. Yet, in order to provide constructive leadership and successfully shape the EU, the two countries must bridge substantial differences and be ready to carry disproportionately high burdens.