Larval house flies, Musca domestica (L.), nutritionally require live bacteria; therefore, all stadia are associated with microbe-rich environments. Larvae live among and ingest bacteria, which are digested via the combined activity of digestive enzymes, lysozyme, and antimicrobial effectors. Some bacteria resist digestion and subsequent proteolytic processes that occur during metamorphosis, and are carried trans-stadially. Adult house flies ingest bacteria directly from septic substrates or indirectly via self-grooming. Ingested bacteria also face digestion in adults; nonetheless, some microbes not only survive, but proliferate and exchange genetic material. The interaction between adult flies and bacteria is critical in determining vector potential. If the fly is ineffective at eliminating ingested microbes, they can be disseminated in excreta. Unlike larvae, adult house flies are highly mobile, synanthropic, and gregarious, moving indiscriminately between septic environments and domestic locations. Flies can travel miles between sites, dispersing pathogens and their antibiotic-resistance and virulence genes. Considered together, these aspects of adult fly biology underlie their role in the epidemiology and ecology of infectious diseases. Studies of house fly biology have fortuitously revealed interesting adaptations to their septic lifestyle that can be exploited in future approaches to fly control and human health. Larval dependence on microbes can be integrated in novel control strategies, which alter habitat microflora. In contrast, larvae can be utilized beneficially to clear manure of pathogens before being used as fertilizer. In addition, house fly defense effectors such as antimicrobial peptides serve as an untapped resource with the potential to generate novel classes of microbicidal therapeutics.