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CD19-specific chimeric antigen receptor (CAR)+ T cells have demonstrated clinical efficacy and long-lasting remissions, concomitant with tolerable normal B-cell aplasia. However, many tumor-associated antigens (TAAs) are expressed on normal tissues, the destruction of which would lead to intolerable toxicity. Thus, there is a need to engineer CAR+ T cells with improved safety profiles to restrict toxicity against TAA-expressing normal tissues. Bioengineering approaches include: (i) targeting CAR+ T cells to the tumor site, (ii) limiting CAR+ T-cell persistence, and (iii) restricting CAR activation. We review and evaluate strategies to engineer CAR+ T cells to reduce the potential of on-target, off-tissue toxicity.