The recent FDA approval of CD19 chimeric antigen receptor (CAR) adoptive T-cell therapy for B-cell leukemias serves to highlight CAR-T cell therapy as a promising treatment approach for refractory cancers. More recently, adoptive transfer of T cells expressing CARs targeting B-cell maturation antigen (BCMA) has had numerous successes in clinical trial with 80-100% of multiple myeloma patients responding to treatment. However, CAR-T-cell therapy still faces several limitations including tumor antigen escape, a circumstance where tumor cells downregulate their surface antigen to avoid detection by CAR-T cells, and T-cell inhibition by cytokines such as transforming growth factor (TGF)-β in the solid tumor environment. These factors can significantly limit the efficacy of CAR-T-cell therapy. To overcome antigen escape, we designed single-chain bispecific CARs (OR-gate CARs) capable of signaling in the presence of two antigens instead of one. Using rational design principles, we constructed and evaluated CD19-OR-CD20 CARs that are able to prevent tumor antigen escape by CD19– leukemia. We further demonstrate that unlike single-input CD19 CARs, CD19-OR-CD20 CARs also prevent the emergence of spontaneous CD19-downregulated tumors in vivo. In a second study, we describe the rapid design and characterization of BCMA-OR-CS1 CARs and demonstrate that BCMA-OR-CS1 CARs can be rationally engineered to prevent antigen escape by BCMA– as well as CS1– myeloma cells. Finally, we explore the utility of the TGF-β CAR, a receptor capable of rewiring inhibitory TGF-β signaling to an activating response, in improving CD20 CAR function in TGF-β-rich environments. We evaluated three different bispecific targeting strategies, OR-gate CAR, DualCAR (co-expressing two receptors in one cells), and CARpool (pooling two different CAR-T cells), and demonstrate that TGF-β CAR-T cells are able to shield neighboring CD20 CAR-T cells from the inhibitory effects of TGF-β.