Exposure of a kidney transplant to warm and/or cold IR results in the activation of multiple pathological processes, including uncontrolled ROS production, activation of immune cells, proinflammatory cytokine production, endothelial and epithelial disintegration, and mitochondrial dysregulation. These effects result in acute loss of kidney function that often resolves following a complete and normal repair. Alternatively, persistent inflammation and further injury, along with defective and inefficient repair processes, can lead to tubular atrophy and fibrosis, which subsequently result in the loss of graft function. In this issue, Aufhauser Jr., Wang, and colleagues demonstrate that sex and estrogen mediate the response from the normal kidney to the IRI kidney. It remains unknown whether these factors affect recovery back toward normal kidney function or the development of atrophic and fibrosed kidney. In addition to estrogen, other factors, such as testosterone, kidney size, recipient size, and sex-specific differences in glomerular filtration rates, could also modulate recovery following IRI. It is not understood how these sex-specific factors interact with other identified pathophysiological mechanisms to determine DGF outcomes. Adapted with permission from Nature Reviews Nephrology (5). DAMPs, damage-associated molecular patterns; TLR, Toll-like receptor.