beta-Thalassemia and sickle cell disease constitute the most common single gene defect in humans and are characterized by absent/reduced and abnormal beta-globin, respectively. Patients with these hemoglobinopathies require chronic blood transfusions and rely on bone marrow transplant for a potential cure. Gene therapy provides a viable alternative by permanent correction of the defect in hematopoietic stem cells, but it has suffered from problems of vector instability, low viral titers, and variable expression of globin genes for more than a decade. This paper reviews the field of gene therapy for hemoglobinopathies with emphasis on the complexities of the beta-globin gene and its regulation, obstacles that have impeded progress, and recent advances in vector technology that will take this field forward toward the goal of successful genetic correction of these devastating diseases.