The aim of this review is to acquaint the reader with the concept of T cell receptor (TCR) gene therapy for metastatic melanoma. We first review antigen choice, followed by gene delivery technology and, finally, we discuss selected clinical applications. To be successful, TCR gene therapy must combine multiple elements and research disciplines. First, there is a need for an understanding of tumor immunology because this is essential in proper antigen choice. Second, gene therapy is a technology-driven field and cutting edge knowledge of protein engineering and gene delivery methods are indispensable. Finally, a dedicated team of physician/scientists and healthcare providers is fundamental to clinical success. TCR gene therapy is now a realistic treatment option for metastatic melanoma. Both tumor regression and on-target/off-tumor toxicities have been observed, which emphasizes the experimental nature of this approach. As with any new medical procedure, future large-scale randomized trials will be necessary to validate this approach, and these are within reason in the next few years. This article is a US Government work and is in the public domain in the USA.