ICKLE CELL ANEMIA, a disease having both he-S molytic and vasocclusive components, has been subjected to intense scrutiny at the clinical, cellular, biochemical, and molecular levels. Yet it remains a perplexing disorder for which exact interrelationships between clinical phenotype and cellular defects and presence of the mutant gene product (hemoglobin S [HbS], p@'"+'a') remain illdefined and the subject of much speculation. In large part, this reflects a profoundly complex pathophysiology that is influenced not only by multiple genetic factors but also by the remarkably pleiotropic effects of the sickle gene itself. The latter ultimately must be explained by definable abnormal molecular behaviors of HbS, of which three are known. One of these, the effect of p chain charge on Hb tetramer assembly, helps determine the proportion of HbS in the nonhomozygous sickling, states.'" Another behavior, the tendency of HbS to polymerize at low oxygen tension and cause the sickling phenomenon, has been assumed to be the dominant factor in disease pathophysiology?'In addition, HbS is unstable, only modestly compared with the classical unstable hemoglobins, but sufficiently to impact on cellular physiology. 6 This instability is hypothesized to explain, at least in part, the myriad abnormalities characteristic of the sickle red blood cell (RBC) membrane (Table 1). This review will discuss the current level of understanding of these membrane defects, including their potential pathophysiologic roles which, depending on defect, vary from unlikely to conceivable to virtually certain. The concluding sections will examine the broader perspective of overall pathophysiology and put forth the hypothesis that the true impact of sickle RBC membrane defects on clinical phenotype is to add a stochastic influence, thereby modulating (and obscuring the theoretical predictability of) the fundamental predisposition to disease severity conferred by genetic determinants of Hb polymerization. Unless specified otherwise, described data refer to RBC from patients homozygous for HbS.