Hematopoietic stem cells (HSCs) function to provide the individual with a continuing supply of blood cells over many decades. To this end, HSCs have evolved unique mechanisms for self-preservation, including resistance to viral infection. Unfortunately, this characteristic may impede the ability to achieve high levels of gene transfer mediated by HIV-based lentiviral vectors. This is an important consideration for gene therapy efforts being undertaken for beta-thalassemia. In particular, the study of beta-thalassemia patients that underwent allogeneic stem cell transplantation and developed stable, long-term mixed chimerism suggests that HSC gene transfer levels of greater than 25% will be needed for a robust therapeutic effect in such patients. Available pre-clinical and clinical trial lentiviral gene transfer studies suggest that improvements are needed to achieve this goal. Here, we review what level of gene transfer is needed in the context of varying degrees of beta-globin deficiency, what level is currently achievable, and the areas of research which may be fruitful in improving the likelihood of success for patients with the severest forms of beta-thalassemia.