Malaria, caused by the apicomplexan parasite Plasmodium, is a major cause of morbidity and mortality throughout the world. This study has focused on the role of the spleen in the control of the blood stage of infection. Three aspects have been examined specifically: the effect of infection on the architecture of the spleen, the role of the spleen in parasite clearance and the formation of B cell memory. Firstly, the effect of infection on the splenic microarchitecture was examined. An essential component of the splenic architecture is the marginal zone (MZ), an area of the spleen that separates the reticuloendothelial red pulp of the spleen from the lymphoid white pulp compartment. Two unique populations of macrophages are found in the marginal zone: marginal zone macrophages (MZM) and marginal metallophilic macrophages (MMM). In the current study, parasitised red blood cells (pRBC) as well as normal RBC located to the MZ thirty minutes after intravenous injection and formed close associations with both MMM and MZM. Eight days after infection, at the time of peak parasitemia, a complete loss of both MMM and MZM was observed. Assays to detect cell death revealed that the loss of both MMM and MZM appeared to occur as a result of apoptosis. The apoptosis was not induced by up regulation of the inflammatory cytokines tumour necrosis factor or interferon-γ and could not be blocked by over expression of the apoptosis inhibitor Bcl2. Significantly, MMM were retained in the absence of CD8+ T cells implicating CD8+ T cells in the loss of MMM. Finally, infection of CD95-/- mice demonstrated that CD95/CD95-ligand (Fas/Fas-ligand) interactions were responsible for some of the CD8+ T cell-mediated loss of MMM. These data provide evidence for a novel interaction between MMM and CD8+ T cellsfollowing infection with Plasmodium. Secondly, the role of the spleen in the control of parasitemia and disease was monitored with an emphasis on determining the role of splenic macrophage populations (MMM, MZM and red pulp macrophages [RPM]) in parasite clearance. A clodronate liposome-mediated macrophage depletion technique was used, and caused a complete loss of all three macrophage sub-populations, as well as 50% of splenic dendritic cells, within 24 hours of administration. Each of the macrophage populations, as well as splenic DC, demonstrated different repopulation kinetics following their depletion from the spleen and these kinetics were utilised to examine each cell population in isolation. RPM depleted mice had significantly higher peak parasitemias than the controls. This peak returned to the level observed in undepleted control animals only after the repopulation of RPM was complete, suggesting that RPM play a role in the control of peak parasitemia following infection. Neither MMM nor MZM played a role in the control of parasitemia. The role of non-splenic macrophages and splenic dendritic cells also was investigated and shown to be insignificant in the absence of splenic macrophages. Finally, the role of RPM in mice immune to infection was investigated and their role shown to be dispensable, with immune mice clearing parasitemia efficiently in the absence of RPM. RPM therefore are important for the innate control of infection with P. chabaudi but are dispensible once adaptive immunity is established. Finally, the role of the spleen in the development of parasite-specific B cell memory was examined. Initial studies demonstrated that germinal centre (GC) development was compromised following infection with P. chabaudi, with an involution of B cell follicles noted early in infection. Adoptive transfer of memory B cells from immunised to naïve mice demonstrated that some protection was conferred on recipient mice by parasite-specific memory B cells. But, the memory B cells could not protect the host from developing parasitemia and did not produce significant amounts of parasite-specific immunoglobulin within seven days of challenge infection. Memory B cells could not be detected ten weeks after infection, indicating that the development, or survival, of parasite-specific memory B cells was compromised. The development of bystander memory B cells was not affected by infection. Finally, long-lived plasma cells were shown to develop in response to infection, although re-exposure of the cells to parasites in the form of recrudescent parasitemia resulted in their loss. This study therefore has identified a defect in the development of long-term, B cell-mediated, protection against infection with P. chabaudi. Each of these factors has significant implications for the understanding of how the spleen contributes to the control of infection with Plasmodium and potential applications for the further development of malaria vaccines and treatment regimens.