Houseflies (Musca domestica L.) ingest microorganisms while living and breeding in filth. Even though houseflies are constantly exposed to septic conditions and harbor microbes in their digestive tract and on their surfaces, they are remarkably impervious to infection and disease. Microbial resistance may be mediated by physical barriers and/or by the activity of immune-responsive agents (microbicidal or microbistatic substances). Surprisingly, little is known about the immune defenses of the housefly. We have constructed an immune-stimulated adult housefly EST library, and identified several Antimicrobial Peptide (AMP) genes of interest. Here we examined the expression of three of these genes, diptericin, defensin and cecropin while mimicking natural microbe exposure (dipping and oral ingestion of Gram-negative or Gram-positive bacteria). Northern analysis showed that houseflies may have a species-specific temporally-regulated response to bacteria. In addition, flies not exposed to pure bacterial cultures do not have a baseline expression of these AMPs, while they clearly are in contact with microbes in their natural environment. A species-specific humoral immune response to high levels of bacteria may be an adaptation to the housefly’s unique and septic niche. As a result, the immune response may be tailored in a way that discriminates between pathogen and commensal, and responds accordingly and efficiently. This specialization could help optimize the use of resources, where flies only would upregulate AMPs when needed. Otherwise, the constitutive expression of AMPs would be metabolically inefficient, since flies are always in contact with microbes in the natural environment, receiving constant (and wasteful) immune stimulation.