Malaria is an infectious, hematologic disease. Plasmodium falciparum infection—on which this review is focused—is one of the most frequent acquired red blood cell (RBC) disorders worldwide.1 During the asexual and sexual intraerythrocytic development of P falciparum, multiple molecular processes contribute to the remodeling of infected and uninfected RBCs,2,3 but how these modifications lead to disease is not entirely clear. The spleen, which filters out altered RBCs,4 is likely an important player in the broad spectrum of clinical manifestations of malaria, in particular, anemia. The aim of this review was to analyze relevant data and hypotheses on how splenic physiology may impact on malaria pathogenesis. Several factors of complexity were taken into consideration, including the dynamic, stage-dependent alterations of RBC induced by P falciparum,2 the diverse mechanisms by which the spleen senses subtle RBC alterations,4 and host and parasite factors that influence clinical outcome. We have focused on the corpuscular, RBC-based dimension of malaria pathogenesis in humans. An improved understanding would help select the best research approaches and interpret new observations in a rapidly evolving epidemiologic context.1