Schematic representation of normal and ineffective erythropoiesis. In normal conditions, erythroblasts generate erythrocytes through a homeostatic balance between proliferation, differentiation, and cell death. In ineffective erythropoiesis, formation of toxic hemichromes leads to apoptosis and cell death of many erythroid precursors, limiting production of erythrocytes. Furthermore, on the basis of several observations (as discussed in the text), we postulate that in β-thalassemia erythroid precursors increase cell proliferation concurrently with reduced cell differentiation. This leads to a net increase in the number of erythroid precursors despite higher rates of apoptosis.