To complete their development in the mosquito, ookinetes—reproductive stages of the malaria parasite Plasmodium—must traverse the midgut epithelium and avoid being detected and lysed by the mosquito complement system (TEP1). Oliveira et al. identified mosquito heme peroxidase (HPX2) and NADPH oxidase 5 (NOX5) as key enzymes that are induced in midgut cells during ookinete invasion that, together with nitric oxide synthase, mediate protein nitration. The HPX2-NOX5 system potentiates nitric oxide (NO) toxicity and is critical for mosquitoes to mount an effective antiplasmodial response. Epithelial nitration and TEP1-mediated lysis appear to act sequentially in parasite killing, and epithelial nitration may help to promote the mosquito complement cascade.