Sickle cell disease and β-thalassaemia are inherited disorders that result from genetic errors in the gene encoding β-globin. Sickle cell disease is characterised by production of abnormal haemoglobin, caused by a single point mutation in the β-globin gene. The abnormal haemoglobin is prone to polymerisation, causing sickling of red blood cells, haemolytic anaemia, vaso-occlusion, end-organ damage, and early death. β-thalassaemia major results from reduced or absent β-globin production caused by various mutations in the β-globin gene, necessitating lifelong red blood cell transfusions for survival. HLA-matched myeloablative allogeneic bone marrow trans plantation has proven curative for these disorders. In sickle cell disease, matched allogeneic bone marrow trans plantation using myeloablative conditioning has been pursued primarily in children, with the proportion of cure in this population now exceeding 95%; similar results have also been achievedfor β-thalassemia major. 1 Most notable among the remaining barriers to broader application of this approach2 are access to an HLA-matched sibling donor, and the anticipated toxic effects of myeloablative conditioning regimens in patients with substantial disease-related organ damage. Inspired by the observation that stable mixed chimerism is sufficient to revert the phenotype to normal in patients with sickle cell disease, 3 researchers began exploring non-myeloablative transplantation for application in adult patients with severe sickle cell disease. Through an HLA-matched sibling regimen using low-dose total body irradiation and sirolimus treatment (because of the ability of this drug to promote T-cell tolerance), stable mixed chimerism and disease reversion was achieved in around 90% of subjects, with few toxic effects. 4 Importantly, a donor engraftment proportion of 20% was sufficient to correct the sickle cell phenotype, 5 showing the utility of non-myeloablative approaches. Unfortunately, only around 10% of patients with sickle cell disease have a suitable HLA-matched sibling donor, 6 meaning that only nine or ten of every 100 patients can be cured by an HLA-matched sibling donor approach. Therefore, alternative donor sources warrant exploration. Efforts to expand the donor pool have included the use of matched unrelated bone marrow and cord blood, but these sources are similarly scarce. 6 Expansion of the donor pool to include half matched (haploidentical) donors has remained a focus, since this approach would allow application of this potentially curative approach to virtually all patients. A major breakthrough in the pursuit of this goal was made in an MHC-incompatible murine transplantation model, which used a novel method of delivery for stan dard immunosuppression. 7 The investigators used conventional high-dose cyclophosphamide, a highly immunosuppressive chemotherapy agent that has long been the standard to condition patients before allo geneic transplantation. However, unlike usual practice, in which cyclophosphamide is delivered before transplantation, they administered the high-dose cyclophosphamide after transplantation to target proliferating alloreactive lymphocytes. This approach is feasible because haemopoietic stem cells are not depleted by this drug, and its use after transplantation improved engraft ment while attenuating graft-versus-host disease (GVHD) in the murine model. 7 Post-transplantation cyclophosphamide treatment subsequently proved highly successful at allowing haploidentical transplantation in haematological malignancy, 8 and set the stage for its trial in sickle cell disease. The first trial in patients with sickle cell disease used non …