Successful reperfusion of an infarct-related coronary artery by primary percutaneous intervention or fibrinolysis during acute ST-elevation myocardial infarction (STEMI) does not always restore myocardial tissue perfusion, a phenomenon termed “no-reflow.” Herein we discuss the pathophysiology of this highly prevalent phenomenon and highlight the most salient aspects of its clinical diagnosis and management as well as the limitations of presently used methods. There is a great need for understanding the dynamic nature of no-reflow, as its occurrence is associated with poor cardiovascular outcomes. The no-reflow phenomenon may lend an explanation to the lack of further improvements in in-hospital mortality in STEMI patients despite decreases in door-to-balloon time. Hence, no-reflow potentially presents an important target for investigators interested in improving outcomes in STEMI.