Successful hand transplantation depends upon an extensive, well-coordinated system with resources and experience in both upper extremity and transplant surgery. This description of such a system is drawn from the experience of the Louisville, Kentucky, Hand Transplant Program, which achieved the world’s first successful hand transplant in January 1999, and which is the only United States program to date. The personnel and components of this system are outlined, with a detailed description of the roles, responsibilities, and interaction between components. This system ensures optimal management throughout recipient selection, psychiatric screening, education and preparation, donor limb retrieval, transplant surgery, immunosuppression administration and monitoring, and post-transplant rehabilitation therapy. The lessons learned from the experience of the Louisville team, and the experiences of the other teams world-wide, are presented to guide organization of future teams participating in this pioneering endeavor.