House flies are carriers of > 100 devastating diseases that have severe consequences for human and animal health. Despite the fact that it is a passive vector, a key bottleneck to progress in controlling the human diseases transmitted by house flies is lack of knowledge of the basic molecular biology of this species. Sequencing of the house fly genome will provide important inroads to the discovery of novel target sites for house fly control, understanding of the house fly immune response, rapid elucidation of insecticide resistance genes, and understanding of numerous aspects of the basic biology of this insect pest. The ability of the house fly to prosper in a remarkably septic environment motivates analysis of its innate immune system. Its polymorphic sex determination system, with male-determining factors on either the autosomes or the Y chromosome, is ripe for agenomic analysis. Sequencing of the house fly genome would allow the first opportunity to study the interactions between a pest insect and its parasitoid (Nasonia vitripennis) at the whole genome level. In addition, the house fly is well placed phylogenetically to leverage analysis of the multiple Dipteran genomes that have been sequenced (including several mosquito and Drosophila species). The community of researchers investigating Musca domestica are well prepared and highly motivated to apply genomic analyses to their widely varied research programs.