Despite the fact that a surgical procedure may have been performed for the appropriate indication and in a technically perfect manner, patients are threatened by perioperative organ injury. For example, stroke, myocardial infarction, acute respiratory distress syndrome, acute kidney injury, or acute gut injury are among the most common causes for morbidity and mortality in surgical patients. In the current review, the authors discuss the pathogenesis of perioperative organ injury, and provide select examples for novel treatment concepts that have emerged over the past decade. Indeed, the authors are of the opinion that research to provide mechanistic insight into acute organ injury and identification of novel therapeutic approaches for the prevention or treatment of perioperative organ injury represent the most important opportunity to improve outcomes of anesthesia and surgery.