In patients presenting with ST-segment elevation myocardial infarction (STEMI) and multi-vessel disease (MVD), the optimal therapy for non-culprit lesions is still a matter of debate. While guidelines discourage a concomitant treatment of infarct- and non-infarct-related arteries, recent studies document advantages of a complete (preventive) revascularization during primary percutaneous coronary intervention. Such an approach, however, may result in overtreatment, because angiography does not provide robust information about the functional severity of MVD. Fractional flow reserve (FFR) measurements can be a valuable guide for non-culprit lesions in acute myocardial infarction, but so far, only the reliability and safety of FFR measurements have been established in this setting. The clinical implications of an FFR-guided treatment strategy in STEMI patients with MVD are currently being tested in a large randomized trial.