This article reviews recent progress in understanding the mechanisms of organ transplant rejection and focuses on studies that suggest new approaches to diagnosis and treatment. The alloimmune response is initiated by recognition of donor major histocompatibility complex antigens by the immune system of the host. During rejection, the upregulation of major histocompatibility complex antigens on donor tissue enhances this recognition phase. Rejection can be prevented by interfering with the interaction of recipient T cells with alloantigens using interventions such as antibodies against major histocompatibility complex proteins or accessory adhesion molecules, peptide-binding antagonists, and genetic alteration of major histocompatibility complex protein expression. Patterns of cytokines produced in the graft following transplantation may be used to distinguish rejection from other causes of transplant dysfunction. In addition, specific antagonists of individual cytokines show promise as antirejection treatments.