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To describe Descemet membrane endothelial keratoplasty (DMEK) complications and strategies for their prevention and management.Five hundred consecutive eyes with DMEK of 393 patients were reviewed in this retrospective study for intraoperative and postoperative complications up to 2 years and for corresponding management.Intraoperative challenges (difficult graft unfolding/positioning, high vitreous pressure, iris root hemorrhage, and Descemet membrane remnants) were encountered in 81 eyes (16.2%). Visually significant graft detachment was the main postoperative complication (34 eyes, 6.8%). Graft failure occurred in 8 eyes (1.6%). Other postoperative complications were an increase of intraocular pressure/decompensated glaucoma in 48 eyes (9.6%), significant cataract in 11 of 124 phakic eyes (8.9%), allograft rejection in 7 eyes (1.4%), cystoid macular edema in 5 eyes (1.0%), microbial keratitis in 2 eyes (0.4%), and retinal detachment in 1 eye (0.2%). Different strategies for prevention and management of these complications have been identified.DMEK shows acceptable rates of complications up to 2 years after surgery, which can be managed successfully. Anticipation of potential challenges and difficulties may aid in modifying intraoperative strategies for predisposed eyes. This knowledge may further minimize complications, in particular, when performing DMEK for an extended spectrum of corneal endothelial disorders.