The hemoglobin disorders of beta-thalassemia and sickle cell disease together constitute the most prevalent group of human monogenic diseases. Although curative allogeneic stem cell transplantation therapy and palliative therapies have been developed for these disorders, the majority of patients still suffer significant morbidity and early mortality. The development of therapeutic approaches based on genetic manipulation of autologous stem cells therefore remains an attractive alternative. In the past 4 years, significant advances have been made toward this goal using lentiviral vectors to obtain high-level expression of complex globin gene cassettes. Therapeutic correction in murine models of both beta-thalassemia and sickle cell anemia has been achieved using this approach. These advances, coupled with progress in the ability to achieve in vivo selection of genetically modified cells, can now be evaluated in the well-developed nonhuman primate autologous transplant model. The goal in these studies is to provide preclinical safety and efficacy data prior to human clinical trials in order to maximize the likelihood of success in the context of an acceptable risk to benefit ratio. Here we review progress in each of these areas.