Several components of malaria infected blood are sensed by the Anopheles mosquito as non-self and will thereby activate robust innate immune responses that participate in the killing of most Plasmodia during their invasion of the midgut epithelium. Microarray-based gene expression analyses of mosquito responses to Plasmodium infection can identify crucial components of its immune defense against the parasite and provide information on the overall impact of the infected blood on the mosquito’s physiological systems. The effectiveness of such high throughput transcriptomic analyses is exemplified by the identification of several genes, such as TEP1, LRIM1 and FBN lectins with confirmed implication in Plasmodium killing. The midgut can be considered the most important mosquito organ with regard to malaria transmission, although many components of this killing process seem to originate from hemocytes and fatbody. To better understand midgut function and identify candidate key players of anti-Plasmodial and anti-microbial defense, we have analyzed its transcriptome with respect to feeding, infection and compartment specific expression. This analysis has provided an unprecedented view of mosquito midgut immune regulatory features and identified several novel putative anti-microbial components.