The no-reflow phenomenon relates to the inability to reperfuse regions of the myocardium after ischemia, despite removal of the large epicardial coronary artery occlusion. The mechanism involves microvascular obstruction. In experimental studies, using markers for flow (thioflavin S, carbon black, microspheres), perfusion defects associated with no-reflow demonstrated ultrastructural evidence of localized endothelial swelling and blebs that appeared to obstruct flow. In humans no-reflow is more complicated due to the microemboli of atherosclerotic debris and thrombi generated by percutaneous coronary intervention. The no-reflow zone expands during the first few hours of reperfusion suggesting an element of reperfusion injury. In animal models, extensive no-reflow was associated with worse infarct expansion. The phenomenon of no-reflow following reperfusion therapy for myocardial infarction in humans has been demonstrated by magnetic resonance imaging, echo contrast agents, thallium, technecium-99m-labeled albumin microspheres, Thrombolysis In Myocardial Infarction (TIMI) scores, and myocardial blush grade. Patients exhibiting no-reflow following reperfusion therapy for myocardial infarction have greater left ventricular dilation and remodeling, more congestive heart failure, shock, and reduced survival. Certain vasodilators (adenosine, nitroprusside, nicorandil, and calcium blockers) are used acutely in the catheterization laboratory and appear to improve no-reflow, but systematic studies on therapy for no-reflow are needed. There is now clinical evidence that no-reflow is a strong predictor of long-term mortality that is independent of and beyond that provided by infarct size. Identifying and treating no-reflow may have important benefits including enhancing delivery of nutrients and cells required for healing and reducing infarct expansion and ventricular remodeling, which ultimately may reduce congestive heart failure and mortality.