Plasmodium falciparum represents one of the strongest selective forces on the human genome. This stable and perennial pressure has contributed to the progressive accumulation in the exposed populations of genetic adaptations to malaria. Descriptive genetic epidemiology provides the initial step of a logical procedure of consequential phases spanning from the identification of genes involved in the resistance/susceptibility to diseases, to the determination of the underlying mechanisms and finally to the possible translation of the acquired knowledge in new control tools. In malaria, the rational development of this strategy is traditionally based on complementary interactions of heterogeneous disciplines going from epidemiology to vaccinology passing through genetics, pathogenesis and immunology. New tools including expression profile analysis and genome-wide association studies are recently available to explore the complex interactions of host-parasite co-evolution. Particularly, the combination of genome-wide association studies with large multi-centre initiatives can overcome the limits of previous results due to local population dynamics. Thus, we anticipate substantial advances in the interpretation and validation of the effects of genetic variation on malaria susceptibility, and thereby on molecular mechanisms of protective immune responses and pathogenesis.