Immune cells can be engineered to kill tumor cells while sparing healthy tissues. Our laboratory developed the first anti-CD19-41BB-CD3zeta chimeric antigen receptor (CAR) to target B-cell lymphoid malignancies. Early clinical trials in B-cell acute lymphoblastic leukemia (B-ALL) with autologous T cells genetically engineered to express this CAR produced dramatic responses, leading to regulatory approval and marketing worldwide. More recent research has led to the development of CAR-T cells to target T-cell malignancies, with encouraging responses in patients with T-ALL. Overall, CAR-T cell therapy has revolutionized the clinical management of patients with ALL, and major clinical responses to CAR-T cells have also been observed in patients with other hematologic malignancies. This success validated the promise of immune cells as anti-cancer agents and encouraged efforts to explore the therapeutic potential of other immune cells.