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.