T lymphocytes can be redirected to recognize a tumor target and harnessed to combat cancer by genetic introduction of T-cell receptors of a defined specificity. This approach has recently mediated encouraging clinical responses in patients with cancers previously regarded as incurable. However, despite the great promise, T-cell receptor gene therapy still faces a multitude of obstacles. Identification of epitopes that enable effective targeting of all the cells in a heterogeneous tumor while sparing normal tissues remains perhaps the most demanding challenge. Experience from clinical trials has revealed the dangers associated with T-cell receptor gene therapy and highlighted the need for reliable preclinical methods to identify potentially hazardous recognition of both intended and unintended epitopes in healthy tissues. Procedures for manufacturing large and highly potent T-cell populations can be optimized to enhance their antitumor efficacy. Here, we review the current knowledge gained from preclinical models and clinical trials using adoptive transfer of T-cell receptor-engineered T lymphocytes, discuss the major challenges involved and highlight potential strategies to increase the safety and efficacy to make T-cell receptor gene therapy a standard-of-care for large patient groups.