Pauling's concern about the spread of sickle cell hemoglobin arose from its relatively high frequency in the human population. By drawing on work performed by other investigators, Pauling stated that the mutation perpetuated because it protected individuals from contracting malaria. Thus, he noted that while some molecular mutations are detrimental, sickle cell trait protected against malaria and benefited these individuals living in malarial areas.

He described three genetic possibilities and translated what each meant for the individual's health as well as explained the genetic make-up of a population procreating in a region with high incidences of malaria. First, people with normal hemoglobin are homozygous dominant and do not exhibit crescent shaped hemoglobin; therefore, they do not have sickle cell trait or sickle cell anemia and additionally are not protected against malaria. Most likely, the majority of these people would die from malaria and therefore stop procreating. Secondly, those born homozygous recessive for sickle cell hemoglobin suffer from sickle cell anemia and typically die young, usually without procreating. Thirdly, those with heterozygous hemoglobin have sickle cell trait and withstand infection from the malaria parasite. These people benefit most in an area with high mortality rates from malaria because they do not contract either disease full-blown.

In areas where malaria is not endemic, Pauling confidently averred that the sickle cell mutation was being removed from the human germ plasma. However, Pauling thought that the natural rate of removal happened too slowly in comparison to the introduction of new mutations. Thus, he promoted eugenic practices as a way to decrease the number of mutations that passed to future generations.