How can we make CAR T cell therapy more effective and safer? Adoptive cellular immunotherapy with chimeric antigen receptor engineered T (CAR-T) cells is currently achieving impressive clinical results in patients with hematologic malignancies. CARs are prototypic synthetic receptors wherein the extracellular input is a cell surface antigen and the intracellular output a composite T cell activating signal providing functional and metabolic cues to determine T cell fate. CAR therapy relies on engineering of T lymphocytes in order to redirect them to kill tumor cells and is the first paradigm of successful clinical use of cellular engineering with synthetic receptors. When targeting CD19, a cell surface molecule found in most leukemias and lymphomas, CAR T cells have produced remarkable clinical results, validating the synthetic biology approach to cancer immunotherapy and consecutively the potential for application to other hematological malignancies and solid tumors. To attain broader relevance, T cell engineering and CAR therapy in particular must achieve effective tumor targeting and tumor elimination with minimal or tolerable toxicity. While therapeutic efficacy of CAR-T cell therapy has been remarkable, a critical mechanism of disease escape includes lack of uniform expression of the target antigen within the clonal tumor populations or downregulation of antigen expression to evade effector cell mediated killing. CD19 CAR-T cell therapy often fails owing to CD19-negative relapse and first clinical trials of BCMA-CAR-T cells have already reported relapses of BCMA negative/low clonal variants. In addition, persistence of CAR-T cells has been inconsistent with some studies demonstrating a correlation between early extinguishing of the CAR-T cell population and the development of resistance. As such, strategies to broaden CAR-T cell mediated targeting of the tumor population and enhance their activation, expansion and durability is critical to develop this potential paradigm changing therapy. The broader applicability of CAR therapy is also impeded by safety concerns regarding the on-target/off-tumor effect of CAR T cells on normal tissues due to the lack of unique tumor-specific surface targets. Although the B-cell aplasia caused by CD19-CAR T cells is an easily manageable clinical situation, this is likely not the case for the majority of potential CAR targets. In addition, the experience of CD19-CAR T cell clinical trials brought into attention the cytokine release syndrome (CRS), mediated by large numbers of tumor-targeted activated T cells, as another safety issue of CAR therapy. Several strategies have already been proposed to regulate CAR T cell function. These include the use of suicide gene strategies, such as the inducible caspase-9 (iCasp9) enzyme, to terminate T cell activity, bispecific small molecules that transiently bridge antigen and CAR T cells, οr dimerizing agents that transiently link the antigen-binding and signaling domains of a CAR. The above studies allow remote temporal control of CAR T cell activity, but they do not address spatial control of antigen engagement and tumor selectivity. To the latter end, affinity tuning or engaging two antigens rather than one provide an interesting paradigm for achieving greater tumor selectivity.