In the past decades, much has been learned about the protective signatures of innate immune responses during the course of infections. However, it is now evident that induction of immune effectors also commonly occurs in the absence of pathogenic cues. Such an event, termed sterile inflammation, has been linked to several debilitating acute and chronic host conditions. Using Drosophila melanogaster as a simple yet powerful model organism, identification of diverse sets of damage-associated molecular patterns and their corresponding surface and/or inside pattern recognition receptors on the cells, as well as elucidation of their significant roles in the host physiology and pathological conditions related to sterile inflammation, have been continuously reported. In addition, revelation of non-pathogenic molecular triggers leading to the orchestration of unnecessary activation of inflammatory responses has been a subject of interest. Here, we review decades of efforts to elucidate the molecular mechanisms responsible in the emergence of sterile inflammation. The characterization of the respective contributing factors, including recent demonstration of pinching as a novel sterile-stimuli in Drosophila, is also discussed.