Primary human activated T lymphocytes were genetically grafted with chimeric T cell receptors (TCR). Three domain single chain (sc-) TCR as well as two chain (tc-) TCR gene constructs were derived from the melanoma-specific cytotoxic human T cell (CTL) clone 82/30, and linked to the CD3-ζ signaling element. Chimeric TCR α and β receptor genes were structurally designed to prevent pairing with endogenous TCR α and β chains in order to prevent the generation of unpredictable immune specificities. After transduction of polyclonally activated human peripheral blood lymphocytes with retroviral vectors harboring the chimeric receptor genes, genetically engineered cells specifically recognized and responded to MAGE-A1 POS/HLA-A1 POS cells. Importantly, each type of transduced T lymphocytes that bound specifically to peptide/MHC complexes also showed specific anti-tumor reactivity as well as lymphokine production. Genetically engineered primary human T lymphocytes expressing chimeric sc-or tc-TCR therefore hold promise for disease-specific therapies.