The human hemoglobin molecule consists of 4 polypeptide chains, one pair designated the α’s and the other the β’s. Sickle cell hemoglobin (Hb S) differs from the normal by a single amino acid substitution at the 6th position in each β chain. It further appears that there is a hydrophobic pocket in each of the a chains which is complementary to the β-6-Valyl region, allowing deoxygenated sickle cell hemoglobin (Hb S) tetramers to stack by hydrophobic interactions. When oxygenated, the β chains move closer to each other by about 5 angstroms and the stacking crumbles because the goodness of fit is lost, This is unsickling by conformational change. There is another unsickling mechanism which involves an entropy change. In 1957 I reported that Hb S has a negative temperature coefficient of aggregation, i.e., a deoxygenated Hb S solution at 0° gels when warmed to 38° C but liquefies reversibly when replaced in the ice bath. Thus, the sickling phenomenon involves a thermal (or endothermic) aggregation of Hb S. The energy of activation for this reaction (ΔH*) is 17.3 kCal mole-1 and the entropy change amounts to 55 e. u. It appears reasonable to assume that the same entropy change is required to set a molecule of water free from the hydration layer about the hydrophobic residues as is required in the melting of ice.