Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties. CD19-specific CARs that comprise CD28 and CD3ζ signaling motifs have induced remarkable responses in patients with refractory leukemia^{, –} and lymphoma and were recently approved by the US Food and Drug Administration. These CARs program highly performing effector functions that mediate potent tumor elimination^, despite the limited persistence they confer on T cells^{, , –,}. Extending their functional persistence without compromising their potency should improve current CAR therapies. Strong T cell activation drives exhaustion^,, which may be accentuated by the redundancy of CD28 and CD3ζ signaling^, as well as the spatiotemporal constraints imparted by the structure of second-generation CARs. Thus, we hypothesized that calibrating the activation potential of CD28-based CARs would differentially reprogram T cell function and differentiation. Here, we show that CARs encoding a single immunoreceptor tyrosine-based activation motif direct T cells to different fates by balancing effector and memory programs, thereby yielding CAR designs with enhanced therapeutic profiles.