Ischemia-reperfusion (IR) injury remains a major contributor to organ dysfunction following transient ischemic insults. Although numerous interventions have been found effective to reduce IR injury in preclinical models, none of these therapies have been successfully translated to the clinical setting. In the context of the persistent translational gap, we systematically investigated the mechanisms implicated in IR injury using kidney donation and transplantation as a clinical model of IR. Whilst our results do not implicate traditional culprits such as reactive oxygen species, complement activation or inflammation as triggers of IR injury, they reveal a clear metabolic signature for renal IR injury. This discriminatory signature of IR injury is consistent with a post-reperfusion metabolic paralysis and involves high-energy phosphate depletion, tricarboxylic acid cycle defects, and a compensatory activation of catabolic routes. Against this background, the picture emerges that clinical IR injury is driven by reductive stress. In this article, we therefore wish to elaborate on the processes contributing to reductive stress in the context of clinical IR injury and provide a better insight in potential clinical therapeutic strategies that might be helpful in restoring the redox balance.