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In the wake of the 10-year anniversary since the introduction of chimeric antigen receptor-T (CAR-T) cell therapies to the market, the field of B cell lymphoma has seen remarkable advances since these therapies first arrived at the bedside in 2017. Modern data from longitudinal readouts attests to the high depth and durability of response to CAR-T therapies in many patients with B cell lymphomas; however, approximately 50% of patients continue to have relapsed/refractory disease even after receipt of conventional CAR-T constructs. In this review, we discuss the mechanisms underlying primary and secondary refractoriness to conventional single-targeting CAR-T therapies for B cell lymphomas and explore the ongoing challenges with existing CAR constructs. We discuss the prospects for adaptable multi-antigen targeting via the use of bivalent CAR and bicistronic CAR functionalities as informed by recent advances in synthetic immunobiology. We explore contemporary efforts, mostly Phase 1 and 2 trials, involving bivalent CAR and bicistronic CAR constructs at the cutting edge of clinical translation. Finally, we propose evidence-based solutions to help improve the translational success of multi-antigen CAR-T therapy, including optimizing construct architecture, expanding the targetable antigen landscape, and improving scalability. These solutions for multi-antigen targeting in next-generation CARs may have substantial benefits in the coming years.