Following the initial successful lung transplants reported by the Toronto Lung Transplant Group in 1986, lung transplantation has evolved into an effective treatment of isolated pulmonary failure and has been performed in more than 20,000 recipients. Increased experience, adjustments, and additions to the surgical technique and improved perioperative care have combined to decrease morbidity and improve survival in lung transplant recipients. An area in which improvements have been made but that continues to cause major morbidity, mortality, and impact on long-term allograft function is primary allograft dysfunction, which occurs in 11 to 60% transplant patients, depending on the diagnostic criteria applied. The basis of this potentially devastating complication is likely ischemia reperfusion injury of the donor allograft with activation of recipient innate immunity. This article discusses mechanisms of primary graft dysfunction in light of recent International Society for Heart and Lung Transplantation consensus definitions, and considers successful strategies for prevention and treatment of primary graft dysfunction.