Red blood cells are vital for tissue homeostasis, display multiple blood group systems, and play key roles in immunity, gas transport, vasodilation, detoxification, and metabolism. We explore the pathophysiological mechanisms of red blood cell alteration and elimination in malaria. In the context of a long and fruitful collaboration between Indonesian-Australian colleagues and BioTiGR team members, our group has contributed to show that red blood cells infected by P. falciparum and P. vivax accumulate in the spleen of asymptomatic subjects in endemic areas (Kho, Qotrunnada et al. 2021) In close collaboration with the French National Reference Center for Malaria, we have confirmed that pitting is a major mechanism of parasite clearance (Ndour, Lopera-Mesa et al. 2015, Wojnarski, Mouri et al. 2019) and is tightly associated with anemia following treatment of malaria with artemisinin derivatives Jaureguiberry, Ndour et al. 2014). The quantification of pitted RBC enables the prediction of post-artemisinin delayed anemia (Ndour, Larreche et al. 2017). Ongoing clinical studies explore immunological and mechanical processes leading to the premature and excessive clearance of red blood cell in patients before and after treatment with antimalarial drugs (Wojnarski, Mouri et al. 2019). Several tools mimicking the spleen sensing and filtering function such as microsphiltration, microfluidic, mice model or ektacytometry (Duez, Holleran et al. 2015, Picot, Ndour et al. 2015) lead us to contribute to the development of innovative assays for gametocytes transmission blocking strategies and to explore the slow clearance of artemisinin resistant parasites.