Ischemia-reperfusion injury of the liver causes severe organ dysfunction after both extended liver resections and liver transplantation. In experimental models, ischemic preconditioning has repeatedly been shown to protect the liver from injury after warm and cold ischemia-reperfusion. Herein, we summarize the experimental and clinical evidence considering protection of tissue by ischemic preconditioning and we conclude that it is now time to initiate prospective randomized multicenter trials, in order to confirm the benefit of ischemic preconditioning for the patients undergoing major liver surgery and liver transplantation.