To describe early challenges and techniques to promote donor tissue adherence in Descemet's stripping with endothelial keratoplasty (DSEK). Price Vision Group, Indianapolis, Indiana, USA. The first 200 consecutive cases of DSEK performed by a single surgeon were analyzed retrospectively. Follow-up was 7 to 20 months for 124 eyes and 2 to 6 months for 76 eyes. The surgical technique consisted of stripping Descemet's membrane and endothelium from the recipient's central cornea and transplanting an 8.0 to 9.0 mm disc of donor endothelium and posterior stroma through a 5.0 mm incision, with sutures used only to close the incision. The most frequent challenge was inadequate donor attachment. Using techniques to remove fluid from the donor-recipient graft interface, the donor detachment rate in the last 64 cases was 6%, with half attributable to patient eye rubbing. Detached grafts were reattached by injecting an air bubble to press the donor against the recipient cornea. There were 7 primary graft failures, with only 1 occurring in the second 100 cases, which primarily used microkeratome-dissected donor tissue. Other complications were infrequent and included pupillary block glaucoma (1), aqueous misdirection syndrome (1), and cataract development in 2 of 27 phakic eyes. The DSEK procedure was performed safely before and after laser in situ keratomileusis (1 each). Early outcomes in the initial 200 consecutive DSEK procedures suggest the technique provides significant advantages over penetrating keratoplasty, including more rapid healing, more predictable refractive outcomes, and better retention of corneal strength and integrity. Although donor adherence was more challenging, DSEK was technically easier and should be less traumatic to anterior chamber structures than earlier posterior grafting techniques.