Liver surgery is associated with many factors, which may affect outcome. Preoperative assessment of patient's general condition, resectability, and liver reserve are paramount for success. The Child–Pugh score and other scoring systems only partially enables to assess the risk associated with liver surgery. The presence of portal hypertension per se is a major risk factor for hepatectomy. Intraoperatively, any attempts should be made to minimize blood loss. Low central venous pressure and inflow occlusion best prevent bleeding. Ischemic preconditioning and intermittent clamping are routinely applied in many centers to protect against long periods of ischemia, although the mechanisms of protection remain unclear. In this review we describe recent advances in activated pathways associated with protection against ischemia. Postoperatively, the best factor impacting on outcome probably resides in experienced medical care particularly in the intensive care setting. Currently, no drug or gene therapy approaches has reached the clinic. The future relies on new insight into mechanisms of ischemia–reperfusion injury.