Patients who present with acute myocardial infarction (AMI) often suffer from coronary multivessel disease (MVD). This condition is associated with an increased mortality rate; it is, therefore, important to improve clinical outcomes through appropriate treatment strategies. Over the past decades, extensive research in AMI and MVD patients has consistently shown that complete revascularization is superior to treatment of the only culprit lesion. Another controversial issue concerns the most appropriate timing for percutaneous coronary intervention in non-culprit lesions. Fractional flow reserve (FFR) is considered the best method for identifying ischemic coronary lesions in the context of acute coronary syndromes, but the detection of vulnerable plaques in non-culprit vessels could further improve clinical outcomes. Intravascular imaging goes beyond physiology and it is potentially useful to recognize patients who are vulnerable, despite negative FFR. Therefore, we analyzed the most relevant studies that have investigated the relationship between physiological indexes and plaque vulnerability. However, ongoing trials aim to clarify how coronary physiology can be combined with the benefits of intracoronary imaging.