Progress toward understanding the biochemical basis of human individuality spans centuries, but tissue rejection remains the primary clinical challenge of organ transplantation. This article highlights the chronology of scientific discoveries made in the quest to overcome the rejection associated with transplantation. The purposes of this review are to raise clinicians' awareness of the advances in surgery, genetics, immunology, and immunosuppression that have contributed to the current knowledge of tissue rejection and to indicate potential new directions in this challenging field.

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