Substantial ischemia-reperfusion injury (IRI) to the transplanted kidney occurs in 30% to 50% of transplantation patients who receive the organ from a deceased donor. IRI usually manifests as delayed graft function (DGF) and, in severe cases, results in primary nonfunction. Previous studies, primarily experimental, have demonstrated sex-specific susceptibility to IRI in kidney and other organs. In this issue of the JCI, Aufhauser Jr., Wang, and colleagues further demonstrate the importance of donor and recipient sex in IRI and elucidate the role of estrogen receptors in a murine model. Furthermore, analysis of data from 46,691 renal transplant patients in the United Network for Organ Sharing (UNOS) database revealed that sex affects DGF outcomes in humans. Manipulation of sex-driven molecular pathways offers a fertile opportunity to increase the number of organs available for transplantation and to reduce IRI in kidney and, likely, other organs.