Sickle cell anemia occurs in individuals who are homozygous for a single nucleotide substitution in codon 6 of the beta-globin gene. This single mutation leads to the formation of abnormal hemoglobin, HbS (alpha2betas[s]2), which is much less soluble when deoxygenated than hemoglobin A (HbA) (alpha2beta2). This insolubility causes aggregates of HbS to form inside sickle erythrocytes as they traverse the circulation. With full deoxygenation, polymer becomes so extensive that the cells become sickled in shape. Yet, even with high oxygen saturation values, quantities of HbS polymer may be sufficient to alter the rheologic properties of sickle erythrocytes in the absence of morphologic changes, and cells can occlude end arterioles, leading to chronic hemolysis and microinfarction of diverse tissues. Ultimately, this process leads to vaso-occlusive crises and irreversible tissue damage. Nonetheless, the spectrum of disease severity even among patients with grossly equivalent hematologic indices suggests that many other factors-including genetic, cellular, physiologic, and psychosocial-play a substantial role in determining the course of this disorder. Of the genetic factors, the level of fetal hemoglobin in particular has been established to favorably modify the clinical manifestations of patients with sickle cell disease and related conditions. Recent advances in the understanding of the molecular and cellular pathophysiology of sickle cell disease, coupled with new insights into the developmental regulation of human globin gene expression, have provided the scientific impetus and clinical rationale to attempt to augment the postnatal production of fetal hemoglobin. Furthermore, contemporary understanding of the quantitative relationship between the extent of HbS polymerization within the red cells and the degree of red blood cell and/or organ pathology has now enabled investigators to predict to what extent this intracellular pathogenic process must be inhibited to achieve clinically significant amelioration of disease manifestation. These areas will be covered in this overview. This is a US government work. There are no restrictions on its use.