The myocardial no-reflow phenomenon is characterized by a reduced antegrade myocardial blood flow despite an open infarct-related artery in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Importantly, no-reflow is known to be associated with unfavorable clinical outcome and prognosis. It is a complex phenomenon and is caused by the variable combination of four pathogenetic components: distal atherothrombotic embolization, ischemic injury, reperfusion injury and susceptibility of coronary microcirculation to injury. As a consequence, appropriate strategies to prevent or treat each of these components are expected to reduce the occurrence of no-reflow. Mechanical and pharmacological approaches performed before, during and after performing myocardial revascularization have been investigated in recent studies, in order to reduce the rate of no-reflow. In this article, we concentrate on the major preventive and therapeutic approaches currently available for the management of the no-reflow phenomenon.