Significance Plasmodium falciparum is responsible for almost all malaria-related deaths and belongs to a family of parasites that infect African apes. In their native habitat, these parasites exhibit strict host tropism, with human P . falciparum having never been found in wild-living chimpanzees and gorillas. Our research provides a molecular explanation for this phenomenon by showing that the interaction between a parasite protein (RH5) and its erythrocyte cell surface receptor (Basigin) is species specific and mirrors the observed host–parasite tropism. Our findings also reveal how a parasite responsible for one of the world’s major health problems has evolved its relationship with the human host and identify specific changes in the Basigin receptor that could make human erythrocytes resistant to infection by P . falciparum .