Adoptive immunotherapy can induce dramatic tumor regressions in patients with melanoma or viral-induced malignancies, but extending this approach to many common cancers has been hampered by a lack of naturally occurring tumor-specific T cells. In this review, we describe recent advances in the genetic modification of T cells using genes encoding cell-surface receptors specific for tumor-associated antigen. Using genetic modification, the many functional properties of T cells, including cytokine secretion and cytolytic capacity, are redirected from their endogenous specificity toward the elimination of tumor cells. Advances in gene design, vectors, and cell production are discussed, and details of the progress in clinical application of this approach are provided.