Methods of enhancing engraftment of donor hematopoietic stem cells (HSCs) by reducing expression or activity of CXCR4 in HSCs is described. HSC are the only cells in the bone marrow that are both pluripotent and long lived. Bone marrow transplantation (BMT) using HSC is an increasingly common medical therapy for severe hematologic cancers and primary hematologic immunodeficiencies. However, for significant HSC engraftment to occur there must usually be pre-transplant conditioning with either irradiation or chemotherapy or both. The technology described herein shows that it is possible to replace HSC without the need for pre-transplant conditioning regimen. It is known that the chemokine receptor CXCR4 plays a critical role in HSC homing to the bone marrow and in HSC quiescence. The inventors have identified a patient in which one copy of CXCR4 had been deleted in a somatic mutation of an HSC and this cell had clonally repopulated the bone marrow. This led to experiments in mice where the inventors clearly demonstrated in a bone marrow transplantation model, that donor cells with a single copy of the Cxcr4 gene repopulate recipient mice much faster and last much longer than donor cells having two copies of the Cxcr4 gene. This technology which shows that HSCs with one copy of the CXCR4 gene have a durable selective advantage in bone marrow repopulation can solve the problem frequently encountered in gene therapy, i.e., the short-lived nature of gene-corrected cells, by utilizing recently discovered gene editing methods that can be used to delete one copy of CXCR4 gene in gene-corrected cells.