The hemoglobin disorders, severe beta-thalassemia and sickle cell anemia, are prevalent monogenetic disorders which cause severe morbidity and mortality worldwide. Gene therapy approaches to these disorders envision stem cell targeted gene transfer, autologous transplantation of gene-corrected stem cells, and functional, phenotypically corrective globin gene expression in developing erythroid cells. Lentiviral vector systems potentially appear to afford adequately efficient gene transfer into stem cells and are capable, with appropriate genetic engineering, of transferring a globin gene with the regulatory elements required to achieve high-level, erythroid-specific expression. Herein are results obtained in use of lentiviral vectors to insert a gamma-globin gene into murine stem cells with phenotypic correction of the thalassemia phenotype. Further, we have developed a drug-selection system for genetically modified stem cells based on a mutant form of methylguanine, methyltransferase, which allows selective amplification of genetically modified stem cells with phenotypic correction even in the absence of myeloablation prior to stem cell transplantation. These advances provide essential preclinical data which build toward the development of effective gene therapy for the severe hemoglobin disorders.