Larvae of the greater wax moth Galleria mellonella have become an increasingly important in vivo model for biomedical research, providing a practical, ethical, and biologically relevant alternative to vertebrate organisms. Its suitability as a model system lies in its low maintenance cost, ease of handling, and ability to survive at both ambient and mammalian body temperatures. Most importantly, G. mellonella exhibits an innate immune system with functional and structural parallels to that of mammals, allowing meaningful insights into infection dynamics and immune responses. This review summarizes the biological and immunological foundations that underpin the use of G. mellonella in experimental research and examines its expanding range of applications. The model has been successfully employed to study microbial pathogenicity, antimicrobial efficacy, host-pathogen interactions, and toxicological responses. In recent years, its use has extended to emerging fields such as nanomedicine, immunomodulation, and environmental biotechnology, reflecting its growing translational value. The adoption of G. mellonella also aligns with current ethical principles in science, particularly the 3Rs framework (replacement, refinement, and reduction), by minimizing the use of vertebrate animals while maintaining robust experimental outcomes. However, certain challenges persist, including the lack of adaptive immunity and the need for methodological standardization to enhance data reproducibility and comparability across laboratories. Collectively, the growing body of evidence supports G. mellonella as a reliable and versatile experimental model that bridges the gap between invertebrate and mammalian systems. Continued methodological refinement and integration with molecular and omics approaches are expected to further consolidate its role in translational and preclinical research. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC.
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