The EU’s new trade strategy promises to advance open strategic autonomy that is to balance the benefits of economic interdependence with growing demands to manage Europe’s exposure to the risks it entails. What explains these shifting priorities? This article situates open strategic autonomy in the theoretical debates of International Political Economy (IPE) literature on economic interdependence and geoeconomics to aid our understanding of the debates ensnaring economic strategy in the EU, but also related debates in the United States, China and elsewhere. This framework, the article argues, helps us understand changing strategic priorities in economic policy by reference to wider structural shifts engulfing the global economy. It then identifies four priority targets of EU economic policy in which (new) autonomous policies are forthcoming: (i) tackle economic distortions; (ii) defend against economic coercion; (iii) link with values and sustainability; and (iv) protect critical assets and supply chains. These observations build towards addressing the main research question: Has open strategic autonomy turned a corner on EU principles of openness, liberalization and international cooperation?