The restoration of blood flow to ischemic tissues causes additional damage, which is termed reperfusion injury. All tissues are susceptible to reperfusion injury, but this susceptibility varies between tissues. Reperfusion has wide clinical relevance. It influences the outcome of patients after myocardial infarction, stroke, organ transplantation, and cardiovascular surgery. Advances in the treatment of reperfusion injury have created an opportunity for plastic surgeons to apply these treatments to flaps and reimplanted tissues. The main putative mechanisms identified in animal models involve leukocyte-endothelium interactions, reactive oxygen species, and the complement system. However, it has become evident that these fundamental biological systems are controlled by many interrelated pathways. Attempts to bypass this complexity have led to a search for the early "upstream" initiating events, rather than the "downstream" cascading events. This contrasts with current clinical efforts that are directed toward hypothermia, intraarterial flushing, and preconditioning. This article outlines the molecular and cellular events that occur during reperfusion injury and then reviews the efforts that have been made to exploit this knowledge for clinical advantage.