Abstract: The first studies of the pharmacological induction of fetal hemoglobin were conducted in patients with sickle cell disease and thalassemia. Although hydroxyurea was approved by the FDA for the treatment of sickle cell disease in 1996, no similar pharmacological agent(s) has been approved for the treatment of patients with thalassemic disorders. The small‐scale studies of the induction of fetal hemoglobin in thalassemia have been generally disappointing. The aim of this report is to provide a critical analysis of the factors that may be responsible for our failure to develop an effective fetal hemoglobin induction therapy for patients with thalassemia. We also describe several areas for future investigation that may be critically important for the development of an effective therapy for thalassemia.