(A) Natural P. falciparum infection begins in humans when Anopheles mosquitos inject sporozoites into the skin and blood. Sporozoites migrate to the liver and invade hepatocytes, where they differentiate into merozoites and replicate asexually without causing symptoms. After seven to ten days, merozoites exit the liver into the bloodstream and begin a 48-hour cycle of asexual replication within erythrocytes. Asexual blood-stage parasites cause disease by triggering inflammation and sequestering in blood vessels of vital organs. A small percentage of blood-stage parasites differentiate into male and female gametocytes — the nonpathogenic sexual forms taken up by mosquitos during blood meals. In the mosquito, gametes fuse and ultimately form sporozoites that migrate to the mosquito salivary gland to complete the life cycle. (B) In this issue, Collins and colleagues describe a new model of malaria transmission from humans to mosquitoes using CHMI. P. falciparum–infected erythrocytes were inoculated intravenously into malaria-naive adults, bypassing the liver and directly establishing a blood-stage infection. The drug piperaquine, which is selectively active against asexual blood-stage parasites, was administered orally seven to eight days later to attenuate the replication of pathogenic asexual parasites while allowing nonpathogenic gametocytes to develop and mature. The transmissibility of gametocytes from humans to mosquitos was assessed either directly by feeding laboratory-reared mosquitoes on the skin of infected subjects or indirectly with assays in which infected blood is fed to mosquitoes through an artificial membrane. All subjects received a curative course of antimalarial drugs at the end of the study.