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Bharat Gurnani,1 Kirandeep Kaur,2 Vaitheeswaran Ganesan Lalgudi,3 Koushik Tripathy4 1Department of Cornea and Refractive Surgery, Sadguru Netra Chikitsalaya, Shri Sadguru Seva Sangh Trust, Janaki-kund, Madhya Pradesh, India; 2Department of Pediatric Ophthalmology, Sadguru Netra Chikitsalaya, Shri Sadguru Seva Sangh Trust, Janaki-kund, Madhya Pradesh, India; 3Department of Cornea, The Ottawa Hospital, University of Ottawa Eye Institute, Ontario, Canada; 4Department of Vitreoretinal and Cataract, ASG Eye Hospital, Kolkata, West Bengal, IndiaCorrespondence: Bharat Gurnani, Consultant, Cataract, Cornea, External Diseases, Trauma, Ocular Surface, Uvea and Refractive Surgery, Sadguru Netra Chikitsalaya, Shri Sadguru Seva Sangh Trust, Janaki-kund, Madhya Pradesh, 485334, India, Tel +919080523059, Email drgurnanibharat25@gmail.comAbstract: Descemet membrane endothelial keratoplasty (DMEK) is a corneal endothelial transplantation procedure with selective removal of a patient’s defective Descemet membrane and endothelium. It is replaced with a healthy donor Descemet membrane and endothelium without a stromal component. Corneal graft rejection can be at the level of epithelium, stroma as well endothelium. DMEK graft rejection is relatively less common than rejection with DSAEK or penetrating keratoplasty, and a good outcome may be achieved with prompt management. The clinical picture of DMEK rejection is usually similar to endothelial rejection in Descemet Stripping Endothelial Keratoplasty (DSEK/DSAEK), which generally manifests as pain, redness, reduction in visual acuity, stromal edema, endothelial rejection line, keratic precipitates at the back of the cornea and corneal neovascularization. However, more subtle forms of rejection or immune reactions are more common in DMEK compared to DSAEK eyes. Early clinical diagnosis, prompt intervention, and meticulous management safeguard visual acuity and graft survival in these cases. Intensive topical steroids form the mainstay in the management of DMEK rejection. Sometimes, oral or intravenous steroids or other systemic immunomodulators may be required. DMEK graft failure can be primary or secondary, and failure usually requires a second procedure in the form of repeat DMEK or DSEK or penetrating keratoplasty (PKP). A detailed literature search was performed using search engines such as Google Scholar, PubMed, and Google books, and a comprehensive review on DMEK rejection was found to be lacking. This review is a comprehensive update on the risk factors, pathophysiology, primary and secondary graft failure, recent advances in diagnosis, prevention of rejection, and updates in the management of DMEK rejection. The review also discusses the differential diagnosis of DMEK failure and rejection, prognosis, and future perspectives considering DMEK failure and rejection.Keywords: descemet membrane endothelial keratoplasty, DMEK rejection, primary graft failure, secondary graft failure, rebubbling