Novel curative therapies using genetic transfer of normal globin-producing genes into autologous hematopoietic stem cells (HSCs) are in clinical trials for patients with sickle cell disease (SCD). The percentage of transferred globin necessary to cure SCD is currently not known. In the setting of allogeneic nonmyeloablative HSC transplants (HSCTs), stable mixed chimerism is sufficient to reverse the disease. We regularly monitored 67 patients after HSCT. After initially robust engraftment, 3 of these patients experienced declining donor myeloid chimerism (DMC) levels with eventual return of disease. From this we discovered that 20% DMC is necessary to reverse the sickle phenotype. We subsequently developed a mathematical model to test the hypothesis that the percentage of DMC necessary is determined solely by differences between donor and recipient red blood cell (RBC) survival times. In our model, the required 20% DMC can be entirely explained by the large differences between donor and recipient RBC survival times. Our model predicts that the requisite DMC and therefore necessary level of transferred globin is lowest in patients with the highest reticulocyte counts and concomitantly shortened RBC lifespans.