Although study of the thalassemias has focussed on possible cure or amelioration by genetic techniques, considerable progress has been made in understanding the underlying pathobiology of these diseases. Better control of childhood infectious diseases has led to a clearer understanding of the frequency and clinical severity of some of these disorders. The striking differences between alpha- and beta-thalassemia are now well documented and the role of oxidant attack in the pathobiology is becoming clearer. Some authors believe that severe beta-thalassemia induces a hypercoagulable state that could be partially caused by scrambling of the phospholipid bilayer of affected erythrocytes. There is growing appreciation that double heterozygosity for hemoglobin E/beta-thalassemia, while causing variable anemia, can produce a clinical condition as severe as Cooley's anemia (beta-thalassemia major). Anemia severity may be related to the extent of oxidant attack on the unstable hemoglobin E. Studies of the hemoglobin Constant Spring variants demonstrate the consequences of accumulating excess unmatched beta globin as well as the unique alpha CS. Studies on marrow erythroid precursors in the beta-thalassemias have already shown accelerated programmed cell death and abnormal assembly of membrane proteins. Such studies in the future will likely further delineate the underlying differences between alpha- and beta-thalassemias.