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Adoptive immunotherapy involving the transfer of autologous tumor or virus-reactive T lymphocytes has been demonstrated to he effective in the eradication of cancer and vitally infected cells. Identification of MHC-restricted antigens and progress in generation of adaptive immune responses have provided new direction for such treatment for severe pathologies such as cancer and autoimmune diseases. Here we review the latest development about the molecular basis of MHC-I/TCR interaction, and its manipulation including enhanced MHC-I expression, modification of peptide and engineered TCR for clinical applications such as vaccine design, tumor therapy and autoimmune diseases. Cellular & Molecular Immunology. 2008;5(3):171-182.