Zuckerkandl and Pauling proposed that evolution was the result of mutations caused by molecular diseases. As a specific example, they argued that humans and primates had lost the ability to manufacture vitamin C, whereas pigs and cattle have not. They also promoted orthomolecular medicine by stating that humans need to ingest vitamin C for optimum health.

In the early 1960s, Pauling also proposed that the amino acid replacement that causes sickle cell anemia is an intermediary step in evolution. Thus, he stated that the replacement of glutamic acid in normal adult hemoglobin with valine in sickle cell hemoglobin aided people from contracting malaria. Pauling thought that eventually the valine in sickle cell hemoglobin would be replaced by a different amino acid, one that would protect people who were homozygous recessive from malaria and would not cause the deadly disease, sickle cell anemia. He stated that Hemoglobin C (which has a lysine at the same locus) was most likely the next evolutionary step to fitter human beings. Four years later more information about genetic synthesis became known, and Pauling noted the fallacy in his theory that sickle cell hemoglobin is an intermediary stage in the evolutionary process between normal adult hemoglobin and Hemoglobin C.