Hemoglobin is a molecule inside the red blood cells of human blood. It has two parts: the heme and the globin. The heme contains iron and transports oxygen from the lungs to the tissues as well as takes carbon dioxide from the tissues to the lungs. Globin, a complex macromolecule, is a protein that helps to keep the hemoglobin liquefied. When hemoglobin combines with oxygen and carbon monoxide, it produces oxyhemoglobin and carbonmonoxyhemoglobin respectively; two substances that Pauling became extensively familiar with during the 1930s and 1940s and continued to investigate structurally until the late 1970s.

In addition to hemoglobin itself, Pauling was also interested in a disease of the blood, sickle cell anemia. Sickle cell anemia is a deadly, hereditary disease that primarily afflicts people of African descent. The disease got this name because the red blood cells of the sufferers bend into a crescent shape when deoxygenated. Oxygenated hemoglobin in people with sickle cell anemia is like that of healthy individuals; it retains its discus shape. Related to sickle cell anemia is the less debilitating affliction, sickle cell trait, in which sufferers have inherited sickle cell hemoglobin from one parent and normal hemoglobin from the other. Pauling learned of sickle cell anemia in 1945 and intermittently conducted research on the disease until his death in 1994.