The hemoglobin variants have a range of stabilities, a number being sufficiently unstable to cause a hemolytic anemia in the heterozygote. These unstable hemoglobins can be readily detected by standard stability tests. The abnormalities in the unstable hemoglobins result in an increased molecular flexibility that affects both the globin chain and the hemoglobin tetramer. The unstable globins are generally synthesized at a normal rate but their distorted structure leads to proteolytic destruction, primarily in the bone marrow. This explains why they are always present in much reduced amounts in the circulation. Evidence from the unstable hemoglobins is that overall globin synthesis at the cellular level continues until there is compensation for the loss of the abnormal chain. Increased flexibility or distortion of the hemoglobin molecule allows more ready oxidation to methemoglobin but, more importantly, there is also rapid conversion of methemoglobin to hemichrome with resultant denaturation and precipitation. The process is accompanied by the release of activated oxygen but there is no evidence that the amounts formed are sufficient to give cell damage. Hemolysis primarily occurs in the microcirculation due to the mechanical obstruction produced by the rigid Heinz bodies.