To date, 78 upper extremity transplants have been performed in 55 recipients around the world. The purpose of this article is to provide an overview of acute and chronic rejection (CR) and to summarize collective insights in upper extremity transplantation. To date, almost all patients experienced AR that is pathophysiologically similar to that in solid organs. The spectre of chronic rejection is just emerging. Upper extremity transplantation has significant potential as a reconstructive option only if efforts are invested in strategies to reduce risks of prolonged immunosuppression and in approaches to better diagnose, monitor and treat AR and CR.