The success of a free microvascular tissue transfer is based on a sufficient microanastomosis which meets the following requirements: a pedicle placed without kinking or twisting, good drainage, a well-defined recipient vessel, integrity of the endothelium, and duration of ischemia. The extent of skin and muscle necrosis increases significantly with increases in ischemia time. Reperfusion of ischemic tissue results in local and systemic damage associated with the release of oxygen free radicals, polymorphonuclear leucocytes, and such endothelial hormones as endothelin-1, EDRF (endothelial-derived relaxing factor), thromboxane, complement, and cytokines. Ischemia-reperfusion disrupts the delicate balance that maintains homeostasis in the microcirculation. This review discusses the clinical and therapeutic aspects of such injury, concentrating on perioperative management in free flap transfer. It points out the possible influence of endothelin-1 on vasospasm at the site of anastomosis, and emphasizes the importance of the endothelium as a highly dynamic network. Finally, future diagnostic and therapeutical aspects are discussed.