Plasmodium infections and the disease malaria remain global health emergencies. Plasmodium parasites replicate within and cause the destruction of host red blood cells, which triggers inflammation and causes the symptoms of malarial disease. Parasite-specific antibody responses that develop following infection are critical for controlling parasite burden and limiting disease severity. CD4+ helper T cells are essential for coordinating these protective antibody responses. However, sterilizing anti-Plasmodium immunity rarely develops, even following repeated infection. We hypothesize this is due to deficient Plasmodium-specific effector and memory CD4+ T cell formation. One of the most critical challenges to developing new immune-based therapies or vaccines against Plasmodium is understanding how or whether long-lived Plasmodium-specific memory CD4+ T cells develop, function and persist following infection. In this project we have developed powerful new cellular, genetic and biochemical approaches that enable direct, high-resolution analyses of bona fide Plasmodium-specific memory CD4+ T cells. These new approaches facilitate our long-term goal to understand the quantity and quality of Plasmodium-specific memory CD4+ T cell responses. Our goal is addressed by three specific aims that test: 1) the phenotype, function and numerical stability of Plasmodium-specific effector and memory CD4+ T cell populations and their impact on protective humoral immunity; 2) how parasite- and host-specific factors regulate the formation of long-lived memory CD4+ T cell responses; and 3) the effector mechanisms and pathways that memory CD4+ T cells use to orchestrate long-lived anti-Plasmodium immunity. Our innovative approaches enable us to establish additional new paradigms for understanding and enhancing CD4+ T cell-dependent anti-Plasmodium immunity. Understanding immune memory formation following Plasmodium infection will enable us to identify and develop new immune-based strategies to limit Plasmodium pathogenesis and disease burden.