Malarial parasite resistance to all known antimalarial drugs is now the norm. Parasites develop resistance through modification of both target and intra-parasitic drug concentrations. We have developed a strategy to develop new therapies that will bypass both these mechanisms of resistance. ENU mutagenesis is used to introduce mutations into the germline of mice that are otherwise susceptible to murine malaria. Mice carrying protective mutations will survive a malarial challenge whereas all other mice will succumb. The genes harbouring the mutations are identified and assessed as potential antimalarial drug targets. At present we have identified over 40 mutations conferring resistance to malarial infection and have 100 resistant lines. Here, we propose novel mechanisms of host resistance to malaria infection. Through our dominant large scale ENU screen for abnormal red blood cell count, 2 novel mutant alleles were identified in spectrin beta (Sptb) gene. All of the mutants exhibit an abnormal red blood cell count, an increase osmotic fragility and a shorter red blood cell (RBC) half-life responsible for hereditary spherocytosis disease. When challenged with the rodent malaria parasite, P. chabaudi and P.berghei, Sptb mutant mice were resistant showing a dramatic increase in survival. We propose that the malaria resistance of Sptb lines is mediated by the deformability and the increase susceptibility to red blood cells clearance from splenic macrophages. This study provides the first evidence that a mutation in Sptb can lead to malaria resistance in mice, and shows that splenic clearance is essential for eliminating Plasmodium spp within Red Blood cells.