We have reviewed the methodology for an accurate quantitation of Hb F in the blood of patients with sickle cell anemia, values observed in hundreds of patients of different (racial or ethnic) backgrounds and with differences in severity of the disease, and the various factors that affect the level of Hb F. The latter include sex, age, genetic background or chromosomal haplotypes, variations in the sequences of the locus control region(s) 5' to the epsilon-globin gene, and the presence of an alpha chain deficiency or alpha-thalassemia. Finally, a few remarks about agents effective in increasing the in vivo Hb F synthesis are also included.