Hematopoietic stem cell-targeted gene therapy using replication-incompetent viral vectors holds promise for the treatment of lympho-hematopoietic disorders. In the last several years, success has been obtained in a series of gene therapy trials for primary immunodeficiencies. Despite low levels of gene transfer into stem cells, these trials were successful because of the marked selective advantage of gene-corrected lymphoid precursors, which allowed reconstitution of the immune system. Because this substantial selective advantage is not endowed upon genetically corrected, immature hematopoietic precursors in the setting of hemoglobin disorders, including beta-thalassemia and sickle cell disease, significantly higher levels of stem cell gene transfer will be needed for clinical success. An additional challenge is the remarkably high level of expression of the corrective vector-encoded globin gene that will be required. In this article, recent developments are reviewed that suggest a successful clinical trial for these hemoglobin disorders will be achieved in the near future.