New insights on Drosophila antimicrobial peptide function in host defense and beyond

•Drosophila AMPs contribute to host defense, notably against Gram-negative bacteria.•Certain AMPs show exquisite specifity against certain pathogens.•Certain AMPs contribute to tumor elimination and may promote neurodegeneration.•Phosphatidylserine exposure could signal aberrant non-self to the immune system.•Both cellular and humoral (AMPs) mechanisms eliminate aberrant host cells. Since the first animal antimicrobial peptides (AMPs) were discovered in insects, Drosophila melanogaster has emerged as a powerful model for their characterization. Drosophila AMPs have been used extensively to monitor the activity of the Toll and Imd NF-κB pathways, but little was known of their precise functions. In this review, we summarize recent findings on the function of Drosophila AMPs not only for antimicrobial defense, but also in the gut, tumor control, and neurology. The integration of these new studies allows a new framework to be drawn that explains how AMPs can contribute simultaneously to microbe killing whilst also regulating important host cellular functions. These functions require that AMPs target not only negatively charged microbes but also aberrant host cells.