The article addresses the question of whether CAR T therapy can cause cancer, in light of recent reports by the FDA and the American Society of Hematology (ASH) regarding T-cell malignancies in CAR T recipients. The authors provide a three-part response to discuss the issue of second primary malignancies (SPMs) after CAR T therapy: 1. **Benefits of CAR T Therapy**: The benefits of CAR T therapy, including improved progression-free survival and overall survival, far outweigh the risks. Even if a causal relationship between CAR T therapy and SPMs were established, the risk is relatively small compared to the potential benefits. 2. **Other Factors for SPMs**: Several factors can contribute to SPMs, such as pretransplant conditioning drugs like bendamustine and lenalidomide, which are known to increase the risk. Additionally, clonal hematopoiesis of indeterminate potential is common in patients before CAR T therapy, and immortal time bias means that patients who develop SPMs are more likely to have achieved complete responses or lived longer due to their primary malignancies. 3. **Current Evidence and Future Research**: While the risk of T-cell malignancies from ex vivo gene therapy was recognized over 15 years ago, modern vector technology has advanced significantly, and large analyses show no evidence of replication-competent lentivirus. However, lymphodepletion drugs used in CAR T therapy can increase the risk of SPMs. Future research aims to identify and operationalize "genomic safe harbors" for CAR insertion to enhance safety. Registry-based studies will provide more insights into risk factors for SPMs in CAR T recipients, and the FDA mandates 15 years of follow-up data to minimize the risk of missed diagnoses. The authors recommend cautious reassurance to patients and referring physicians, emphasizing that current evidence does not support a significant new risk of T-cell malignancies in CAR T recipients. They conclude that the benefits of CAR T therapy clearly outweigh the risks in patients with hematologic malignancies and should not be understated.The article addresses the question of whether CAR T therapy can cause cancer, in light of recent reports by the FDA and the American Society of Hematology (ASH) regarding T-cell malignancies in CAR T recipients. The authors provide a three-part response to discuss the issue of second primary malignancies (SPMs) after CAR T therapy: 1. **Benefits of CAR T Therapy**: The benefits of CAR T therapy, including improved progression-free survival and overall survival, far outweigh the risks. Even if a causal relationship between CAR T therapy and SPMs were established, the risk is relatively small compared to the potential benefits. 2. **Other Factors for SPMs**: Several factors can contribute to SPMs, such as pretransplant conditioning drugs like bendamustine and lenalidomide, which are known to increase the risk. Additionally, clonal hematopoiesis of indeterminate potential is common in patients before CAR T therapy, and immortal time bias means that patients who develop SPMs are more likely to have achieved complete responses or lived longer due to their primary malignancies. 3. **Current Evidence and Future Research**: While the risk of T-cell malignancies from ex vivo gene therapy was recognized over 15 years ago, modern vector technology has advanced significantly, and large analyses show no evidence of replication-competent lentivirus. However, lymphodepletion drugs used in CAR T therapy can increase the risk of SPMs. Future research aims to identify and operationalize "genomic safe harbors" for CAR insertion to enhance safety. Registry-based studies will provide more insights into risk factors for SPMs in CAR T recipients, and the FDA mandates 15 years of follow-up data to minimize the risk of missed diagnoses. The authors recommend cautious reassurance to patients and referring physicians, emphasizing that current evidence does not support a significant new risk of T-cell malignancies in CAR T recipients. They conclude that the benefits of CAR T therapy clearly outweigh the risks in patients with hematologic malignancies and should not be understated.