Malaria is a complex disease, dependent on multiple host/parasite/vector interactions. This tripartite system offers numerous opportunities for disease-preventing interventions, but also creates robustness that undercuts ‘magic bullet’ expectations. Our interdisciplinary TransMalariaBloc will approach the challenge of malaria control in the field from this perspective. It utilizes the enormous recent advances in our molecular understanding of the three implicated organisms without prejudicing which targets or process will prove most suitable to transmission blocking (TB). In a feedback loop of experimentation and modeling, we will address the potential and actual impact of TB drugs and remedies which supplied to human hosts, can block transmission from an infected bloodmeal; TB vaccines which elicit human antibodies to antigens essential for transmission; and immune mosquitoes, genetically modified (GM) to achieve natural or synthetic refractoriness. Recent studies suggest that vector/parasite genotypic interactions determine the success or failure of Plasmodium falciparum to infect mosquitoes. In this perspective, we will assay genome-wide polymorphisms in both parasites and vectors to dissect important genotype*genotype interactions, thus guiding the development of effective TB vaccines, drugs and remedies, and GM mosquitoes. Effectiveness of TB interventions, especially via use of GM mosquitoes, depends on the balance of infection and resistance costs. Components of this balance will be explored, to foresee the dynamics of vectorial competence in mosquito populations and assess the efficacy of TB strategies, as well as guide the development of new targets. Again, interaction between modeling and experimentation will be a powerful combination. This proposal represents an ambitious, but feasible approach, spanning from molecular to population and environmental levels, to optimizing TB interventions for malaria control in endemic areas.