The causative agent of malaria, Plasmodium, has to undergo complex developmental transitions and survive attacks from the mosquito's innate immune system to achieve transmission from one host to another through the vector. Here we discuss recent findings on the role of the mosquito's innate immune signaling pathways in preventing infection by the Plasmodium parasite, the identification and mechanistic description of novel anti-parasite molecules, the role that natural bacteria harbored in the mosquito midgut might play in this immune defense and the crucial parasite and vector molecules that mediate midgut infection.