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Delayed graft function (DGF) is a form of acute kidney injury (AKI) and a common complication following kidney transplantation. It adversely influences patient outcomes increases the financial burden of transplantation, and currently, no specific treatments are available. In developing this form of AKI, activation of the renin-angiotensin system (RAS) has been proposed to play an important role. In this review, we discuss the role of RAS activation and its contribution to the pathophysiology of DGF following the different stages of the transplantation process, from procurement and ischemia to transplantation into the recipient and including data from experimental animal models. Deceased kidney donors, whether during cardiac or brain death, may experience activation of the RAS. That may be continued or further potentiated during procurement and organ preservation. Additional evidence suggests that during implantation of the kidney graft and reperfusion in the recipient, the RAS is activated and may likely remain activated, extrapolating from other forms of AKI where RAS overactivity is well documented. Of particular interest in this setting is the status of angiotensin-converting enzyme 2, a key RAS enzyme essential for the metabolism of angiotensin II and abundantly present in the apical border of the proximal tubules, which is the site of predominant injury in AKI and DGF. Interventions aimed at safely downregulating the RAS using suitable shorter forms of angiotensin-converting enzyme 2 could be a way to offer protection against DGF., Competing Interests: D.B. is a consultant for AstraZeneca, Renibus, and Advicenne; has ownership interest in Angiotensin Therapeutics Inc; received research funding from AstraZeneca, Feinberg Foundation, and the National Institutes of Health; and patents or royalties and founder of Angiotensin Therapeutics Inc. D.B. is the coinventor of patents: “Active Low Molecular Weight Variants of Angiotensin Converting Enzyme 2” and “Soluble ACE2 variants and uses therefore.” The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)