Engineering a patient's own T cells to express tumor-targeting heterodimeric T-cell receptors (TCRs) is a promising therapeutic strategy. Even so, development of this method has been undermined by unintended dimerization of endogenous and exogenous TCR chains, resulting in hybrid receptors that lead to off-target effects and autoimmunity, and by suboptimal expression of the introduced tumor-specific TCR. Provasi et al. overcome these obstacles by first disrupting the endogenous TCR a and b chains using zinc-finger nucleases. Subsequent expression of tumor-targeting TCR chains delivered by lentiviral vectors produced high levels of expression of the expected antigen-specific TCRs. Tested in a series of experimental mouse models, the engineered cells did not set off an auto-immune response and protected the mice against leukemia. (Nat. Med. advance online publication, doi:10.1038/nm.2700, 1 April 2012)