Malaria is the most serious and widespread parasitic disease of humans and is arguably the commonest disease of red blood cells (RBCs). Malaria has exerted a powerful effect on human evolution and selection for resistance has led to the appearance and persistence of a number of inherited diseases. After parasite invasion, RBCs are progressively and dramatically modified. New structures appear inside the RBC and novel parasite proteins are exported to the erythrocyte cytoplasm and membrane skeleton. Radical biochemical, morphological, and rheological alterations manifest as increased membrane rigidity, reduced cell deformability, and greater adhesiveness for the vascular endothelium and other blood cells. Numerous protein-protein interactions between the malaria-parasite and the host RBC are important for many aspects of parasite biology and the pathogenesis of malaria. In addition, there are many other parasite proteins located within the infected red cell and at the membrane skeleton, for which no precise functional roles have yet been elucidated. Sequencing and annotation of the complete genome of Plasmodium falciparum, the production of proteomic and transcriptomic profiles of parasites, and the development of a transfection system for the asexual stage of the parasite are all recent achievements that should advance understanding of the molecular mechanisms that underlie the parasite-induced functional alterations in red cells.