The thalassemias are hereditary anemias caused by mutations that affect the synthesis of the globin, the protein component of the hemoglobin. Thalassemias produce massive public health problems in many parts of the world. Thalassemias are classified according to which particular globin chain produced in a reduced amount, which may lead to an imbalance in globin chains synthesis, ineffective erythropoiesis, hemolysis, and eventually to a variable degree of anemia. The main types of thalassemias are the a, b, db, d, and gd. The a and b-thalassemias are the most common classes, and b-thalassemia is the most important and widely spread type which causes severe anemia in the homozygous and compound heterozygous states. Thalassemias are clinically classified according to their severity into thalassemia major requiring a regular blood transfusion throughout life, thalassemia intermedia characterized by anemia but not of such severity as to require regular blood transfusion, and thalassemia minor or trait which is the symptomless carrier state. The severity of the clinical syndrome of b-thalassemia depends on the type of mutation in the β gene. Blood transfusions are gradually introduced by physician to suppress thalassemia manifestation. However regular blood transfusion inevitably leads to iron overload. Evidences of marked iron deposition in the liver, heart, pancreas, thyroid, parathyroid, adrenal, renal medulla, bone marrow, and spleen are commonly reported. This parenchymal iron loading is the major cause of morbidity and mortality in the severe b-thalassemias. The normal adolescent growth spurt fails to occur, and hepatic, endocrine, and cardiac complications producing a variety of clinical problems including diabetes, hypoparathyroidism, adrenal insufficiency, and liver failure will take place. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. In the last decades, several programs, aimed at controlling the birth rate of thalassemia newborns by screening and prenatal diagnosis of populations with high risk of β- thalassemia, have been successful accomplished. Bone marrow transplantation has offered a definitive cure for the fraction of patients with available donors and the introduction of the oral iron chelators deferasirox that preferentially chelates hearth iron. More recently, major advances have being made in the discovery of critical modifier genes, that regulate of HbF (fetal hemoglobin) and hemoglobin switching.