Over the past 20 years, advances in the management of ST segment elevation myocardial infarction have focused on the rapid achievement of patency in the infarct-related artery. The limitation of this therapeutic strategy has been exposed with the development of diagnostic techniques to assess coronary microcirculation, including myocardial contrast echo, magnetic resonance imaging, myocardial perfusion grading, and the coronary flow wire. These methods have expanded our ability to understand and recognize the no-reflow phenomenon, which describes the absence of tissue perfusion despite epicardial coronary artery patency and flow. Although the mechanisms responsible for the development of no reflow are not fully understood, the end result is microvascular damage produced by microvascular obstruction or reperfusion injury. Ideally, early recognition of the no-reflow phenomenon should provide an opportunity for therapeutic intervention designed to augment tissue perfusion and maintain the viability of myocardium at risk. A number of pharmacologic agents are being used in conjunction with percutaneous transluminal coronary angioplasty in an attempt to improve microvascular perfusion. These include IIb/IIIa receptor antagonists, adenosine, verapamil, and the experimental agent nicorandil. In the new millennium, the emphasis of reperfusion therapy is being shifted downstream from its exclusive focus on the epicardial artery to assuring normal blood flow at the tissue level. This article will review the epidemiology, pathophysiology, and therapeutic approach to this vexing clinical problem.