The figure is a schematic of the natural selection that occurs with the gene for sickle hemoglobin in areas endemic for P. falciparum malaria. The left-hand side of the panel shows the situation in people with two genes encoding normal hemoglobin A (designated by red). These people have a significant chance of dying of acute malarial infection in childhood. In contrast, people with two genes for sickle hemoglobin (shown in green) are likely to succumb to sickle cell disease at an early age, as shown in the right-hand side of the figure.

In the center are people with sickle cell trait who possess one gene for normal hemoglobin and one gene for sickle hemoglobin. These children are more likely to survive their initial acute malarial attacks than are people with two genes for normal hemoglobin. Also, they suffer none of the morbidity and mortality of sickle cell disease. Therefore, the people with sickle cell trait are more likely to reach reproductive age and pass their genes on to the next generation.

The genetic selective scenario in which a heterozygote for two alleles of a gene has an advantage over either of the homozyous states is called "balanced polymorphism". A key concept to keep in mind is that the selection is for sickle cell trait. A common misstatement is that malaria selects for sickle cell disease. This is not true. A person with sickle cell disease is at an extreme survival disadvantage because of the ravages of the disease process. This means that a negative selection exists for sickle cell disease. Sickle cell trait is the genetic condition selected for in regions of endemic malaria. Sickle cell disease is a necessary consequence of the existence of the trait condition because of the genetics of reproduction.