The thalassemias are hereditary hemolytic anemias characterized by decreased or absent synthesis of one of the globin subunits of the hemoglobin molecule. In the α-thalassemias, decreased synthesis of α-globin results in accelerated red cell destruction because of the formation of insoluble HbH (β4) inclusions in mature red cells. The greater clinical severity of the β-thalassemias reflects the extreme insolubility of α-globin, which is present in relative excess because of decreased β-globin synthesis. Insoluble α-globin precipitates in developing erythroblasts, leading to marked ineffective erythropoiesis. Severe disease does occur among the α-thalassemias, but only when no α-globin is produced. The thalassemias are among the most common genetic diseases of man. The high gene frequency results from a selective advantage of the thalassemia phenotype in heterozygotes, where it protects from severe malaria. A quantitative decrease in globin synthesis without a qualitative change in the gene product must reflect an alteration in gene function or regulation. The recent explosion in our understanding about gene organization and structure has been matched by characterization of several specific thalassemia mutations at the level of DNA sequence. Many well studied examples of mutations that alter specific steps in gene expresion, e.g., gene transcription, RNA processing, and mRNA translation, will form the focus for this review. The current status of several approaches to the treatment of severe thalassemia will also be summarized. Modifications of the transfusion regimen and use of subcutaneous desferrioxamine have resulted in improved conventional treatment, but the problem of ultimately fatal iron overload may not yet be completely solved. Bone marrow transplantation and pharmacologic stimulation of HbF production are now being explored as potentially useful, but still highly experimental approaches, for treatment of severe β-thalassemia. Insertion of normal globin genes into bone marrow stem cells of thalassemic individuals offers the possibility of cure of this disease. Gene therapy is not yet practical, although many successful strategies are being employed to transfer genes into cells in tissue culture; the application of these techniques to the problem of thalassemia in the future seems quite probable.