Although the success rate of microvascular replantation and revascularization procedures has increased steadily since the 1960s, some replanted tissues do not reperfuse despite technically adequate arterial anastomoses. This failure of microvascular perfusion is termed no reflow. Much research has been directed toward discovering the etiology of no reflow since it was first described 25 years ago. Three pathophysiologic processes have been identified as playing a central role in the development of no reflow: intracellular calcium overload, oxygen-free radical medicated damage, and altered arachidonic acid metabolism. The first tissue believed to be injured irreversibly by these processes is the endothelium, which leads to dysfunction of the parenchymal cells. All 3 pathways are interrelated extensively, which allows for pharmacologic intervention at many different steps. Agents that have been shown to be beneficial in preventing no reflow include calcium channel blockers, prostaglandin analogs, thromboxane synthesis inhibitors, vasodilators, thrombolytics, and many antioxidants. Although they have been shown to be effective in various laboratory models, additional investigation is necessary before these treatments can be established in clinical use.