In the century since the discovery of the ABO blood groups, numerous associations between ABO groups and disease have been noted. However, the selection pressures defining the ABO distributions remain uncertain. We review published information on Plasmodium falciparum infection and ABO blood groups. DNA sequence information dates the emergence and development of the group O allele to a period of evolution before human migration out of Africa, concomitant with P falciparum's activity. The current geographic distribution of group O is also consistent with a selection pressure by P falciparum in favor of group O individuals in malaria-endemic regions. We critically review clinical reports of ABO and P falciparum infection, documenting a correlation between disease severity and ABO group. Finally, we review published data on the pathogenesis of P falciparum infection, and propose a biologic model to summarize the role of ABO blood groups in cytoadherence biology. Such ABO-related mechanisms also point to a new hypothesis to account for selection of the Le(a-b-) phenotype. Taken together, a broad range of available evidence suggests that the origin, distribution, and relative proportion of ABO blood groups in humans may have been directly influenced by selective genetic pressure from P falciparum infection.