The paucity of suitable lung donors and the high early mortality as the result of primary graft failure remain major challenges in pulmonary transplantation. There is evidence that the lung is injured in the donor by the process of brain death and often is made unusable or fails posttransplantation after amplification of the injury by the process of ischemia-reperfusion. An understanding of the mechanism of donor lung injury could lead to the development of new treatment strategies for the donor to reduce lung injury, increase the number of donors with acceptable lungs, and improve the results of transplantation. The pathophysiology of brain death is complex and involves sympathetic, hemodynamic, and inflammatory mechanisms that can injure the lung. The literature is reviewed, and these mechanisms are discussed together with their possible interrelations.