The cornerstone of the treatment of ST-segment–elevation myocardial infarction (STEMI) is to reduce infarct size (IS) as much as possible and thereby improve patient outcomes. This intended reduction in IS is currently pursued with timely reperfusion of both the affected epicardial vessel and the subtended microcirculation. However, restoration of “normal“ epicardial flow does not guarantee the restoration of normal microcirculatory perfusion. Suboptimal myocardial perfusion after the achievement of epicardial patency is a frequent and frustrating clinical conundrum colloquially called “no reflow” and is associated with profound coronary microvascular injury, larger IS, and strongly with worse clinical outcomes.