The function of donor organs after transplantation depends on the quality of procurement and preservation. The absence of oxygen and nutrients damages tissues, swiftly triggering cell death and impairing viability and function. Ischemic injury in the absence of interventions is most intense at normothermic conditions, hence the traditional approach of rapid procurement techniques to cool organs, thereby decreasing metabolic demand and subsequent cellular injury. More injury occurs at reperfusion, when reestablishment of circulation triggers a sterile immunologic cascade, further destroying tissues.1 The transition from physiological circulation to organ explantation in living donation and donation after brain death is usually controlled with hypothermic solutions. Organs procured from donors after circulatory death (DCDs) are prone to more extensive injury. The scarcity of organs has necessitated a constant push of the boundaries of organ donation and acceptance. In DCDs, withdrawal of life support before donation is linked to prolonged periods of warm ischemia, thus increasing organ injury and worsening outcomes. Normothermic regional perfusion (NRP) has been developed, diminishing warm ischemia times and avoiding some of its detrimental effects by restoring circulation immediately after DCD donor asystole with extracorporeal membrane oxygenation (ECMO).2 However, use of NRP in DCDs remains restricted to cases of controlled cardiac arrest. Capacity for organ donation in cases of uncontrolled cardiac arrest with functional tissue preservation has remained elusive. Substantial progress has been made recently.3 Notably, Andrijevic et al have reestablished whole-body circulation and oxygenation after circulatory death through the use of a novel perfusion system and a cytoprotective perfusate previously used to restore circulation and cellular activity in the brain.4 The perfusion technology, OrganEx, includes hemodiafiltration, a centrifugal pump, and a pulse generator, along with synthetic hemoglobin (Hemopure), priming solutions, pharmacological compounds with cytoprotective potential, and a specialized dialysis exchange fluid. The goal was to study whether this system could rescue cells and tissues from the deleterious effects of a lack of blood flow and oxygenation. To test this, the authors induced cardiac arrest in pigs and removed them from ventilator support, thereby initiating a warm ischemic period of 1 h. Groups of pigs were then exposed to either 6 h of (a) OrganEx perfusion, (b) ECMO perfusion, or (c) additional warm ischemia. OrganEx perfusion restored pulsatile flow in major conduit arteries and examined organs, enhancing tissue oxygen delivery while reducing metabolic acidosis and eliminating postmortem rigidity and lividity. Furthermore, OrganEx offset cellular injury and delayed the cell death triggered by oxygen deprivation. In contrast, in the ECMO group, they observed collapsed vessels, widespread deterioration of cytoarchitectural features, and extensive signs of ongoing cell death, comparable to observations in pigs without reestablished circulation. In addition to restoring circulatory and structural homeostasis, OrganEx facilitated recovery of vital organ functions. OrganEx perfused brains, kidneys, and hearts restored cellular glucose uptake. In the heart, QRS complexes and ventricular contractions reemerged during perfusion. Albumin secretion rebounded in livers, and kidneys demonstrated increased proliferative and molecular responses. Single-nucleus RNA sequencing of the organs demonstrated that many cellular repair, metabolism, and cell death suppression processes were transcriptionally active. However, there was minimal urine production and no signs of global neural network activity in the brain. Although OrganEx appeared to halt and even reverse cellular demise compared with ECMO, further investigation is required to understand the relative contribution of the OrganEx components not used in ECMO. The role of hemodiafiltration, pulsatile flow, and the perfusate itself will require exploration because each component is likely contributing to some of the observed improvements. For example, normothermic perfusion regularly employs dialysis,5 but the beneficial effects of dialysis used in tandem with ECMO in donors are unknown. Pulsatile flow can maintain cellular metabolism and contribute to endothelial protection, thus improving organ perfusion with the OrganEx approach, in contrast to the nonpulsatile flow used in ECMO.6 Finally, the perfusate used with OrganEx contains pharmacologic inhibitors of ischemia-reperfusion injury, whereas ECMO uses “only” blood and normal saline. Thus, the current work does not delineate whether the presence of blood and the absence of OrganEx perfusate components exacerbate injury even beyond the histologic damage seen subsequent to prolonged ischemia in the absence of interventions. To further define mechanisms of cellular recovery, additional experimental control groups are thus needed (eg, ECMO and dialysis, or ECMO primed with OrganEx perfusate). Another observation requiring more clarity is how the ECMO group can have both decreased flow and decreased pressure given that the experimental approach targeted arterial pressures to the same level as in the OrganEx group. The recovery from cellular demise after oxygen deprivation at body temperature realized with the OrganEx technology is a remarkable achievement with many implications in medicine and biomedical research, including transplantation. It will thus be interesting to delve further into the ischemic time threshold at which cellular recovery is unattainable. Moreover, what minimal and maximal perfusion times are needed to attain and sustain recovery of key cellular functions? Are these times organ specific? It will also be relevant to consider whether the OrganEx perfusate can be used in ex vivo organ perfusion under both hypothermic and normothermic conditions, extending viability before transplantation. All those aspects will have undeniable impacts on transplantation, potentially also facilitating the utilization of organs from donors subsequent to uncontrolled cardiac arrest. The recovery of cellular functions in the brain will certainly require a more detailed analysis. At the same time, rapid expansion of NRP use in DCD donors has initiated a controversial ethical debate over whether the technique takes steps that potentially obscure the divide between graft optimization and patient resuscitation. Those aspects have raised concerns by some that this approach may challenge the irreversibility of death or the “irreversible cessation of circulatory and respiratory functions” component of its legal declaration in the United States.7 Overall, tissue recovery after extended ischemia times afforded by OrganEx technology may increase DCD organ availability by extending the time in which organs can safely be procured from donors. The approach raises additional questions that will need to be tackled.