AbstractT cell receptor (TCR) gene transfer is a convenient method to produce antigen‐specific T cells for adoptive therapy. However, the expression of two TCR in T cells could impair their function or cause unwanted effects by mixed TCR heterodimers. With five different TCR and four different T cells, either mouse or human, we show that some TCR are strong – in terms of cell surface expression – and replace weak TCR on the cell surface, resulting in exchange of antigen specificity. Two strong TCR are co‐expressed. A mouse TCR replaces human TCR on human T cells. Even though it is still poorly understood why some TCRα/β combinations are preferentially expressed on T cells, our data suggest that, in the future, designer T cells with exclusive tumor reactivity can be generated by T cell engineering.