Conceptual and technological advances in infectious disease diagnosis and treatment have changed the face of medicine. The development of effective interventions against complex pathogens such as the Plasmodium parasite is, however, challenged by our inadequate understanding of host-pathogen immunity. Immunity to infection requires the dynamic interaction of complex networks of a large number of molecular components. Contemporary reductionist approaches (gene-by-gene or protein-by-protein) have insufficient scope to properly elucidate these interactions. Accordingly, we are pursuing a holistic whole organism strategy using a range of genome-based technology platforms with specimens from individuals naturally or experimentally exposed to malaria to understand the immune mechanisms and antigenic targets of protective immunity to malaria. A particular focus is on the molecular profiling of adaptive immunity to Plasmodium in humans and animals using systems immunology, which combines immunology with cutting-edge omics-based technologies, bioinformatics and computational sciences. This allows the human immune response to infection to be interrogated at a level of detail previously restricted to mouse models. We are taking advantage of unique human experimental infection models as well as field studies in disease-endemic areas in individuals who are or are not protected against disease. Using this approach, we have identified novel cell subsets, microRNAs and mRNAs that associate with parasite control. We anticipate that this holistic approach will facilitate the development of new strategies to combat the Plasmodium parasite and eradicate malaria.