Abstract: β-thalassemia is a hereditary hemolytic disorder caused by mutations or deletions in the β-globin gene, leading to reduced or absent synthesis of the β-globin chain. It is the most widely distributed and most common monogenic disorder worldwide. Thalassemia is predominantly found in the Mediterranean region, the Middle East, North Africa, the Indian subcontinent, Southeast Asia, and Southern China, with particularly high incidence rates in Guangxi, Guangdong, and Hainan in China. β-thalassemia major, the most severe form, is fundamentally characterized by severe anemia, transfusion dependence, and complications from iron overload due to chronic transfusions. The current mainstay maintenance therapy involves regular blood transfusions and iron chelation. However, patients face high monthly costs for these treatments. Allogeneic hematopoietic stem cell transplantation is the curative option available, but its widespread application is limited by donor scarcity, risks of graft-versus-host disease and immune rejection, and the substantial expenses associated with the procedure and immunosuppressive medications. The severe symptoms and long-term management impose a heavy burden on patients, their families, and society. In recent years, ex vivo gene therapy using autologous hematopoietic stem cells transduced with lentiviral vectors carrying a functional β-globin gene or edited by gene-editing technologies has emerged as an alternative curative approach for β-thalassemia major. Most current clinical trials for β-thalassemia major employ this ex vivo strategy to achieve transfusion independence, although it still presents several limitations. This review summarizes the disease burden of β-thalassemia major, the latest advances in gene therapy, and potential future directions for gene therapy development.