Hydroxyurea has emerged as a useful therapy in sickle cell disease. It is a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides. Hydroxyurea has been shown to induce the production of fetal hemoglobin (HbF) in patients with sickle cell anemia, with associated diminished morbidity and, likely, mortality in these patients. Any HbF is good in SCD, although it is estimated that levels of 20 percent HbF are required to substantially reduce the sickling propensity of red cells and to modulate disease severity. The majority of patients with SCD respond to hydroxyurea with a more than two-fold increase in HbF levels; in some patients the percent of HbF exceeds 10 or 15 percent, but it is not uniformly distributed in all cells, i.e. has a hetero-cellular rather than a pan-cellular distribution. The mechanism through which hydroxyurea augments fetal Hgb is incompletely characterized. An additional benefit of hydroxyurea may be through effects on the nitric oxide (NO) system. Recently, members of our group found that hydroxyurea therapy is associated with the intravascular and intra-erythrocytic generation of NO, and that NO increases HbF expression via the guanylyl cyclase/cGMP dependent pathways.