Gene therapy trials for sickle cell disease have been showing great promise, even offering hope of a cure. But in early 2021, the trials ground to a halt after reports of blood malignancies in two people in a trial sponsored by bluebird bio. Investigations later concluded that the gene therapy delivery vectors were likely not to blame, and the trials have resumed, including one at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. But the mystery remains: Why did these malignancies occur? And should these cases deter people with sickle cell disease from entering gene therapy trials?