β-thalassemia is the most intensely studied genetic disorder that continues to pose a significant public health challenge in spite of the innumerable and potentially effective treatment options. Specifically, homozygous deletion or subfunctional mutation of the gene contributing the β chains of the adult hemoglobin results in a clinical form referred to as β-thalassemia major. This form of β-thalassemia is hard to treat. The treatment of β- thalassemia major is currently based on the following main principles: a) regular blood transfusion with treatment aimed at reducing tissue deposition of iron; b) modulation of the fetal hemoglobin (HbF) switch to restart the production of HbF; c) allogeneic hematopoietic stem cell transplantation; and d) approaches aimed at preventing or treating the common complications of β-thalassemia major like infections, cardiac and hepatic dysfunction and osteoporosis. The past decade has witnessed path-breaking advances with regard to all of these therapeutic alternatives. For example, iron chelators like desferrioxamine, deferasirox and deferiprone have led to an increased patient compliance and decreased rates of iron deposition; more accurate diagnostic methods based on the magnetic resonance imaging have helped to better define and plan management of iron overload; several classes of HbF inducers have been identified and exciting opportunities are being recognized based on a combination of these inducers; a plethora of agents are available for the prevention and treatment of common complications; and, most significantly, phenomenal advances have been made in the direction of gene therapy of β- thalassemia major. In this chapter, we present a compiled account of the recent advances on these fronts and also conjecture on the possible future directions these achievements are likely to take.