Chimeric antigen receptor (CAR) T cells use re-engineered cell surface receptors to specifically bind to and lyse oncogenic cells. Two clinically approved CAR-T?cell therapies have significant clinical efficacy in treat-ing CD19-positive B cell cancers. With widespread interest to deploy this immunotherapy to other cancers,there has been great research activity to design new CAR structures to increase the range oftargeted cancers and anti-tumor efficacy. However, several obstacles must be addressed before CAR-T?cell therapies can be more widely deployed. These include limiting the frequency oflethal cytokine storms, enhancing T-cell per-sistence and signaling, and improving target antigen specificity. We provide a comprehensive review of recent research on CAR design and systematically evaluate design aspects ofthe four major modules of CAR structure: the ligand-binding, spacer, transmembrane, and cytoplasmic domains, elucidating design strate-gies and principles to guide future immunotherapeutic discovery.