Thyroid hormone and its cognate receptor (TR) have been implicated in the production of red blood cells. Here, we show mice deficient for TRα have compromised fetal and adult erythropoiesis. Erythroid progenitor numbers were significantly reduced in TRα−/− fetal livers, and transit through the final stages of maturation was impeded. In addition, immortalized TRα−/− erythroblasts displayed increased apoptosis and reduced capacity for proliferation and differentiation. Adult TRα−/− mice had lower hematocrit levels, elevated glucocorticoid levels, and an altered stress erythropoiesis response to hemolytic anemia. Most TRα−/− animals contained markedly altered progenitor numbers in their spleens. Strikingly, 20% of TRα−/− mice failed to elicit a stress erythropoiesis response and recovered very poorly from hemolytic anemia. We conclude that an underlying erythroid defect exists in TRα−/− mice, demon-strating the importance of TRα to the erythroid compartment.