Plasmodium falciparum is responsible for more than 200 million cases of clinical malaria and half a million deaths every year. Falciparum malaria disproportionally affects young children as individuals living in endemic areas gradually acquire immunity against the disease. Despite the importance of acquired immunity to malaria, we still know very little about the molecular and cellular bases of this dynamic process. Here, we propose to analyze blood samples collected during a five-year longitudinal study in Mali to comprehensively characterize the role of the host and parasite gene expression in the acquisition of immunity against falciparum malaria. First, we will compare the transcriptomic responses to a first P. falciparum infection of children who then remain free of symptoms for five years, to those of matched children who developed many clinical malaria episodes. Second, we will analyze the changes in gene expression occurring, in the same children, over five successive malaria episodes to better understand the molecular changes accompanying the gradual acquisition of immunity. Overall, our studies will provide a unique perspective on the role of the parasite and host gene expression in the acquisition of immunity against clinical malaria and could provide important information to guide the development of more efficient malaria vaccines.