Chimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All  approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in non-physiological regulation of CAR-signaling and  limits their accessibility due to logistical challenges, high costs and biosafety requirements. Random gene transfer modalities pose a risk of malignant transformation by insertional mutagenesis. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T-cells and natural killer (NK) cells with  CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation  domain into the human CD3? (CD247) gene, functional CAR fusion-genes are  generated that exploit the endogenous CD3? gene as the CAR’s activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR- expression and redirection of various immune cell types, including conventional T cells, TCR?/d T-cells, regulatory T-cells, and NK-cells. In T-cells, CD3? in-frame  fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3?-CD19-CAR-T-cells exhibited comparable leukemia control to T cell receptor alpha constant (TRAC)-replaced and  lentivirus-transduced CAR-T-cells in vivo. Tuning of CD3?-CAR-expression levels significantly improved the in vivo efficacy. Notably, CD3? gene editing enabled redirection of NK-cells without impairing their canonical functions. Thus, CD3? gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes.