Beta-thalassemia is one of the most prevalent autosomal disorders in the world. Mutations in the HBB gene underlie deficiencies in hemoglobin production, which can interfere with oxygen delivery resulting in wide range of disease severity. Although >535 mutations have been characterized in the HBB gene, beta-thalassemia is broadly classified into three groups, based on clinical severity: beta-thalassemia major, beta-thalassemia intermedia and beta-thalassemia minor. In this article we review: 1) the molecular and biochemical basis of beta-thalassemia; 2) clinical features; 3) the range of common molecular variants of beta-thalassemia in a subset of geographic regions within the Indian Subcontinent and the Middle East; 4) potential molecular diagnostics; and 5) current and future treatments. We suggest that efforts to more completely characterize the HBB mutation distribution in high-risk areas, such as the Indian Subcontinent and the Middle East, may lead to improved diagnosis with earlier and more effective intervention strategies.