Beta thalassemia (β-thalassemia) is an autosomal recessive genetic disease with many genes involved. It is a heterogeneous disorder caused by variations in the inactivation mechanism of the Beta-globin (β-globin) genes. Despite seemingly similar genotypes, the patients with Beta-thalassemia have a remarkable variability in anaemia, growth development, and hepatospleenomegaly and transfusion requirements. The genetic factors may differ in each race or ethnic group for therapy and prevention. Despite remarkable successes in the treatment of Beta-thalassemia in the past decades, it is still the leading cause of death and premature disability in developed and developing countries. Possible factors that influence the severity of anaemia in thalassemia may be inherited or non-inherited. The inherited factors include the type of β-thalassemia, coinheritance of alpha thalassemia (α-thalassemia) and factors that stimulate fetal hemoglobin (HbF) production. In this chapter, respective contributions of known modifiers and also the pharmaceutical agents currently in use and under clinical trials for regulating the globin gene expression will be discussed.