Organ transplantation is a victim of its own success. In view of the excellent results achieved to date, the demand for organs is escalating whereas the supply has reached a plateau. Consequently, waiting times and mortality on the waiting list are increasing dramatically. Recent achievements in organ bioengineering and regeneration have provided proof of principle that the application of organ bioengineering and regeneration technologies to manufacture organs for transplant purposes may offer the quickest route to clinical application. As investigators are focusing their interest on the utilization and manipulation of autologous cells, ideally the end product will be the equivalent of an autograft such that the recipient will not require any antirejection medication. Achievement of an immunosuppression-free state has been pursued but has proven to be a difficult odyssey since the early days of the transplant era, yet an immediate, stable, durable, and reproducible immunosuppression-free state remains an unfulfilled quest. As organ bioengineering and regeneration has shown the potential to meet both the needs for a new source of organs that may eclipse the increasing organ demand and an immunosuppression-free state, advances in this field could become the new Holy Grail for transplant sciences.