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Objective To understand and overcome the challenges associated with moving life-urgent payloads using unmanned aircraft. Background data Organ transportation has not been substantially innovated in the last 60 years. Unmanned aircraft systems (UAS; ie, drones) have the potential to reduce system inefficiencies and improve access to transplantation. We sought to determine if UASs could successfully be integrated into the current system of organ delivery. Methods A multi-disciplinary team was convened to design and build an unmanned aircraft to autonomously carry a human organ. A kidney transplant recipient was enrolled to receive a drone-shipped kidney. Results A uniquely designed organ drone was built. The aircraft was flown 44 times (total of 7.38 hours). Three experimental missions were then flown in Baltimore City over 2.8 miles. For mission #1, no payload was carried. In mission #2, a payload of ice, saline, and blood tubes (3.8 kg, 8.4 lbs) was flown. In mission #3, a human kidney for transplant (4.4 kg, 9.7 lbs) was successfully flown by a UAS. The organ was transplanted into a 44-year-old female with a history of hypertensive nephrosclerosis and anuria on dialysis for 8 years. Between postoperative days (POD) 1 and 4, urine increased from 1.0 L to 3.6 L. Creatinine decreased starting on POD 3, to an inpatient nadir of 6.9 mg/dL. The patient was discharged on POD 4. Conclusions Here, we completed the first successful delivery of a human organ using unmanned aircraft. This study brought together multidisciplinary resources to develop, build, and test the first organ drone system, through which we performed the first transplant of a drone transported kidney. These innovations could inform not just transplantation, but other areas of medicine requiring life-saving payload delivery as well.