The malaria parasite's complex journey through the mosquito vector provides multiple opportunities for targeting with recombinant effectors at different developmental stages and different host tissues. We have designed and expressed transgenes that efficiently suppress infection by targeting the parasite with multiple independent endogenous and exogenous effectors at multiple infection stages to potentiate suppression and minimize the probability for development of resistance to develop. We have also addressed the fitness impact of transgene expression on the mosquito. We show that highly potent suppression can be achieved by targeting both pre-oocyst stages by transgenically overexpressing either the endogenous immune deficiency immune pathway transcription factor Rel2 or a polycistronic mRNA encoding multiple antiparasitic effectors and simultaneously targeting the sporozoite stages with an anti-sporozoite single-chain antibody fused to the antiparasitic protein Scorpine. Expression of the selected endogenous effector systems appears to pose a lower fitness cost than does the use of foreign genes.