A few years into the post-Cold War era, the adoption by the US of sanctions legislation geared to penalise foreign firms investing in countries under Washington’s sanctions elicited resistance from European allies, which coalesced into an unusually unified response by the EU. This response notably combined elements from the Community trade toolbox and that of the répertoire of the Common Foreign and Security Policy (CFSP). In the event, a negotiated solution to the conflict could be reached. However, secondary sanctions resurfaced some fifteen years into the new millennium, most conspicuously in the framework of the settlement of the Iran nuclear proliferation crisis, pitting Brussels and Washington again. Notably, the use of secondary sanctions after Trump administration’s withdrawal from the Joint Comprehensive Plan of Action threatened its survival altogether, jeopardising a key CFSP goal. This chapter explains the background to the current political conflict over secondary sanctions, illuminates the political dynamics that inform it, presents the tools developed for addressing the dilemma they pose to the EU and assesses recent developments.