The favorable effects of high levels of fetal hemoglobin (Hb F) in sickle cell disease have been recognized for several decades. This has been an important incentive for the development of therapeutic agents that increase Hb F production. 5-Azacytidine, the first such agent in clinical use, was proposed based on a molecular understanding of the role of DNA methylation in globin gene regulation. Controversy over the mechanism of Hb F induction by 5-azacytidine led to the identification of hydroxyurea as another agent that can increase Hb F production. Although the clinical benefit of hydroxyurea has been demonstrated in a randomized clinical trial, greater increases in Hb F are clearly needed for optimal therapeutic effect. Butyrates also increase Hb F levels, and their use in combination with hydroxyurea appears to be synergistic. Now that multiple therapeutic agents are available for Hb F induction, the use of combination therapy to increase Hb F levels sufficiently to prevent all the complications of sickle cell disease has become a realistic goal.