Chimeric antigen receptor (CAR) T cell therapy is a promising cancer treatment that has recently been undergoing rapid development.However,there are still some major challenges,including precise tumor targeting to avoid off-target or "on-target/off-tumor" toxicity,adequate T cell infiltration and migration to solid tumors and T cell proliferation and persistence across the physical and biochemical barriers of solid tumors.In this review,we focus on the primary challenges and strategies to design safe and effective CAR T cells,including using novel cuffing-edge technologies for CAR and vector designs to increase both the safety and efficacy,further T cell modification to overcome the tumorassociated immune suppression,and using gene editing technologies to generate universal CAR T cells.All these efforts promote the development and evolution of CAR T cell therapy and move toward our ultimate goal-curing cancer with high safety,high efficacy,and low cost.