The article reviews the molecular mechanisms underlying the innate immune defense of *Drosophila melanogaster* against microbial infections. The fly's defense mechanisms include physical barriers, local and systemic immune responses, and specialized hemocytes. Key components of the immune system, such as antimicrobial peptides (AMPs) and reactive oxygen species (ROS), are produced by epithelial tissues and the fat body. The Toll and Imd signaling pathways play crucial roles in regulating these defenses, with the Toll pathway being activated by Gram-positive bacteria and fungi, and the Imd pathway being activated by Gram-negative bacteria. The recognition of pathogens by pattern recognition receptors (PRRs) such as peptidoglycan recognition proteins (PGRPs) and Gram-negative binding proteins (GNBPs) is essential for initiating the immune response. The article also discusses the role of other pathways, such as the JAK/STAT and JNK pathways, in immune regulation. Additionally, it highlights the importance of epithelial immunity, including the production of AMPs and ROS, and the cellular response mediated by hemocytes. The review emphasizes the conservation of these immune mechanisms across metazoans and their potential applications in understanding and combating infections in higher organisms.The article reviews the molecular mechanisms underlying the innate immune defense of *Drosophila melanogaster* against microbial infections. The fly's defense mechanisms include physical barriers, local and systemic immune responses, and specialized hemocytes. Key components of the immune system, such as antimicrobial peptides (AMPs) and reactive oxygen species (ROS), are produced by epithelial tissues and the fat body. The Toll and Imd signaling pathways play crucial roles in regulating these defenses, with the Toll pathway being activated by Gram-positive bacteria and fungi, and the Imd pathway being activated by Gram-negative bacteria. The recognition of pathogens by pattern recognition receptors (PRRs) such as peptidoglycan recognition proteins (PGRPs) and Gram-negative binding proteins (GNBPs) is essential for initiating the immune response. The article also discusses the role of other pathways, such as the JAK/STAT and JNK pathways, in immune regulation. Additionally, it highlights the importance of epithelial immunity, including the production of AMPs and ROS, and the cellular response mediated by hemocytes. The review emphasizes the conservation of these immune mechanisms across metazoans and their potential applications in understanding and combating infections in higher organisms.