Anopheles gambiae mosquitoes are major vectors of Plasmodium falciparum, a protozoan parasite that causes the most severe form of human malaria in Africa. With an estimated 250 million infected people every year and another 3.3 billion at risk, malaria remains one of the biggest scourges of humanity. One of the promising approaches to fight malaria is the control of vector competence that determines the ability of a mosquito to transmit the disease. The fact that mosquito strains that are resistant to the parasites can be selected indicates that genetic factors in mosquitoes limit parasite development.Here we propose to use laboratory infection models to decipher the complex genetic networks that sustain mosquito resistance to P. berghei and P. falciparum. In these models, genotype-to-genotype interactions and environmental variability are limited, two features that are essential to efficiently dissect the genetic control of a complex trait. The parallel identification of loci conferring resistance to P. berghei and to P. falciparum will be crucial to unravel the conserved and species-specific aspects of mosquito parasite interactions at the molecular level. We will further evaluate the contribution of the identified genes and networks to vector competence in natural mosquito populations. Because resistance naturally occurs in mosquito populations, this project has implications for the design of novel strategies and/or for the improvement of existing ones to reduce malaria transmission.