General mechanisms by which hemoglobinopathies may attenuate the pathogenesis of falciparum malaria. *(A) Restriction of red blood cell (RBC) invasion or intraerythrocytic growth, thereby suppressing parasite densities in vivo; *(B) interference with parasite-derived mediators of pathogenesis, including those involved in the binding of parasite-infected RBCs (iRBCs) to extracellular host receptors; *(C) modulation of innate host defenses to favor protective, anti-inflammatory responses over those that drive pathogenic, pro-inflammatory responses; *(D) enhancement of adaptive cell-mediated and humoral immune responses that clear iRBCs from the blood.