Insects' resistance to infectious agents is essential for their own survival and also for the health of the plant, animal and human populations with which they closely interact. Several of the major human diseases are spread by insects and are rapidly expanding as a result of the development of insecticide resistance in vectors and drug resistance in parasites. A vector insects' permissiveness to a pathogen, and hence the spread of the disease, will largely depend on the compatibility of the molecular interactions between the two species and the capability of the insect immune system to recognize and kill the pathogen. The innate immune system comprises a variety of components and mechanisms that can discriminate between different microorganisms and mount specific responses to control pathogenic infections. An impressive body of knowledge on the insects' innate immunity has been generated from studies in the model organism Drosophila. These studies are now guiding the exploration of the immune system in the vector mosquito of human malaria, Anopheles, and its implication in the elimination of parasites. Anopheles immune responses have been linked to parasite losses and some refractory mosquitoes can kill all parasites through specific defence mechanisms. The recently sequenced Drosophila and Anopheles genomes provide a detailed and comparative view on their immune gene repertoires that in combination with post-genomic analyses is used to further dissect the complex mechanisms of Plasmodium killing in the mosquito.