A genetically selected strain of the mosquito Anopheles gambiae, the major vector of malaria in sub-Saharan Africa, is able to encapsulate and kill Plasmodium ookinetes after they have penetrated the midgut cells and come to rest between the midgut epithelial cells and the surrounding basal lamina. The genetic basis of this phenotype has now been examined by high-resolution mapping using microsatellite loci. Results of this mapping indicate that three genes contribute to this phenotype, with one gene on the left arm of chromosome 2 accounting for the most of the effect. These genes, called Pen1, Pen2, and Pen3 (for Plasmodium encapsulation genes 1, 2 and 3) have also been physically localized to relatively small and well defined regions of the polytene chromosome complement. Strategies for cloning these genes by genetic and physical mapping methods are discussed.