Ischemia-reperfusion injury (IRI), a “two-hit” phenomenon in which organs suffer from abrupt blood flow interruption followed by a paradoxical second hit after restoration of the flow, remains a significant deterrent to liver transplantation, due to its associated morbidity and mortality in graft recipients. A unique characteristic of IRI in organ transplantation is the prolonged times which organs are subject to ischemia, as well as the presence of two different kinds of ischemia, cold and warm. Combination of both, such as in donation after circulatory death (DCD) grafts, has been shown to be deleterious to postoperative liver function and correlate directly with long-term complications such as biliary strictures and graft loss. Liver IRI induces damage of hepatocytes and liver sinusoidal endothelial cells (SECs), which is regulated by several molecular pathways. Adenosine triphosphate (ATP) depletion during ischemia leads to metabolic impairment and lactic acid buildup, followed by mitochondrial dysfunction and a shift from oxidative phosphorylation to glycolytic pathways. Once oxygen supply has been restored by reperfusion, the metabolic shift leads to accumulation of reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs). Damaged and activated SEC and liver macrophages (Kupffer cells) promote neutrophil migration and platelet activation by releasing pro-inflammatory mediators such as cytokines and chemokines. Migrated neutrophils secrete ROS, further promoting cell death. Activated platelets induce a reduction of microcirculation by vasoconstriction and thrombosis in the sinusoid. In the clinical setting, three main therapeutic strategies can be applied to protect the DCD liver graft from ischemic damage and to improve postoperative function: (1) minimizing the ischemia time, (2) providing thrombolytic therapy during the transplant procedure, and (3) carrying out machine perfusion. In particular, ex-situ machine perfusion is a promising approach for the protection from IRI with improved hepatic function and a reduction of biliary injury.