Infection by Plasmodium falciparum malaria was one of the major driving forces for the selection of various genes, some of which might be involved in protection against this infection. The human leukocyte antigen (HLA) system is a highly polymorphic supergene complex with extensive diversity across different populations. In areas traditionally endemic for malaria for centuries, there seems to be some selection of certain HLA alleles that may somehow be involved in protection against the infection. One of the major conundrums is the lack of homogeneity in the HLA alleles selected by P. falciparum across different populations. Various factors like microheterogeneity in parasite species, genetic drift in parasitic antigens, varying intensities of transmission, different polymorphisms of red cell antigens, and diversity in the HLA system have exerted selection pressure, which probably determined the emergence of different dominant HLA antigens in different endemic populations. The complex life cycle of P. falciparum, with different antigens becoming important at different phases of the cycle and invasion of different tissues causing different clinical manifestations of the same disease, is also another significant factor contributing to a selection pattern. Evolutionary selection pressure probably selected different HLA antigens for modulations of different components of the disease as well as the severity of the disease. A coevolution, where the parasite polymorphisms meet the host heterogeneity, is likely to have occurred, resulting in the selection of a few HLA antigens associated with P. falciparum infection. Data might have been overwhelmed by the noise of additional selection pressure exerted by other infectious agents prevalent in endemic areas of P. falciparum malaria.