Adoptive immunotherapy with tumor-specific T lymphocytes has demonstrated clinical benefit in some cancers, particularly melanoma. Yet isolating and expanding tumor-specific cells from patients is challenging and there is limited ability to control T-cell affinity and response characteristics. T-cell receptor (TCR) gene therapy, in which T lymphocytes for immunotherapy are redirected using an introduced rearranged TCR, has emerged as an important alternative. Successful TCR gene therapy requires consideration of a number of issues, including TCR specificity and affinity, optimal gene therapy constructs, types of T cells administered, and the survival and activity of the modified cells. In this review we highlight the rationale for and experience with TCR gene therapy as well as new approaches to enhancing it.