Primary percutaneous coronary intervention is the preferred reperfusion strategy for the management of acute ST-segment elevation myocardial infarction. No reflow is characterized by the inadequate myocardial perfusion of a given segment without angiographic evidence of persistent mechanical obstruction of epicardial vessels. Both pharmacologic and device-based strategies have been tested to resolve coronary no reflow. This article provides an updated overview of the no-reflow phenomenon, discussing clinical evidence and ongoing investigations of existing and novel therapeutic strategies to counteract it.