Patients with severe beta thalassemia or sickle cell anemia would benefit significantly if HbF production could be consistently augmented. The imbalance in globin synthesis characteristic of thalassemia could be partially corrected by increased gamma globin synthesis. Reduction of intracellular HbS concentration by replacement with HbF reduces the polymerization potential of intracellular sickle hemoglobin, decreasing the sickling """"""""propensity"""""""" of red cells from such individuals. Several classes of substances stimulate HbF synthesis including cytotoxic agents (e.g. hydroxyurea), hematopoietic growth factors (erythropoietin) and agents that modify DNA or chromatin structure (e.g. 5-Azacytidine or sodium butyrate, respectively). We have previously shown that either sodium butyrate or erythropoietin increases the level of HbF synthesis achievable with hydroxyurea. These data, obtained in a rhesus model, formed the basis for ongoing clinical trials. Four patients with sickle cell anemia treated with a combination of hydroxyurea and erythropoietin have achieved substantial levels of HbF production. Current efforts are focusing on optimizing the schedule of drug administration and expanding the studies to include additional patients. A collaboration has been established to study the effect of phenlbutyrate, a compound with activities similar to these of sodium butyrate, in stimulating fetal hemoglobin production in patients with thalassemia.