Despite discoveries concerning the molecular abnormalities that led to the thalassemic syndromes, it still is not known how accumulation of excess unmatched alpha-globin in beta thalassemia and beta-globin in alpha thalassemia leads to red blood cell hemolysis in the peripheral blood, and in the beta thalassemias particularly, premature destruction of erythroid precursors in marrow (ineffective erythropoiesis). Oxidant injury may cause hemolysis, but there is no evidence that it causes ineffective erythropoiesis. Hemoglobin E/beta thalassemia is now a worldwide clinical problem. The reasons underlying the heterogeneity and occasional severity of the syndrome remain obscure. Ineffective erythropoiesis now appears to be caused by accelerated apoptosis, in turn caused primarily by deposition of alpha-globin chains in erythroid precursors. However, it is not clear how alpha-globin deposition causes apoptosis. The author uses new observations on the control of erythropoiesis to provide a framework for studying the enhanced thalassemic erythroid apoptosis.