Over the years, the Schamel and Minguet groups have collaborated in BIOSS and CIBSS to develop new chimeric antigen receptor (CAR) formats aimed at enhancing our understanding of TCRs and improving cancer immunotherapy. This review summarizes our work alongside that of others. Engineered T cells expressing CARs have revolutionized the treatment of hematological cancers by combining antibody-like tumor-antigen binding with the signaling functions of the TCR ζ chain and co-stimulatory receptors. While successful for certain cancers, new CAR formats are needed to reduce side effects and expand efficacy to solid tumors. Advances in understanding TCR signaling and identifying unique signaling motifs have led to CAR designs that outperform existing options in preclinical and clinical settings. In this Perspective, we examine the rationale behind these innovative CAR designs.