ABSTRACT Retrotransposons are the most abundant genetic elements in almost all animal cells, making up 38% of the human genome. Their activation inherently leads to DNA damage and mutations, and this activity is increasingly appreciated to cause numerous human diseases. Despite their abundance and fundamental impacts on host physiology and pathology, the study of retrotransposons remains an underexplored area of biomedical research. Using new tools and technologies developed by my team, in the long-term, we aim to understand how retrotransposon activity is developmentally regulated, and what are the function and impact of their developmental activation to the hosts under physiological and pathological conditions. Our early progress revealed an unexpected convergence among developmental retrotransposon activation, host immunity, and antiviral response. These results lead to our central hypothesis that developmentally programed retrotransposon activation primes the immune system to grant the hosts a long-term protection against future pathogen infections. Toward this hypothesis, we have discovered that Gypsy retrotransposon selectively becomes active in the newly regenerating tissues during Drosophila metamorphosis. We have also found that Gypsy activation triggers the production of antimicrobial peptides (AMPs), the effectors of innate immunity. Excitingly, we further learned that suppressing Gypsy activation during metamorphosis leads flies to succumb to viral infection at adulthood. Guided by these strong preliminary data, we propose to pursue three Specific Aims to characterize this Gypsy activation mechanism and to uncover how Gypsy signals AMP production and ultimately promotes an antiviral response: (1) Characterize how Gypsy activity is regulated during animal development. (2) Elucidate the molecular mechanisms by which Gypsy activation primes host innate immunity. (3) Define the long-term impact of Gypsy activation on combating pathogens. Collectively, our proposed research will broadly impact the field by identifying new mechanisms that control retrotransposons and characterizing the influence of retrotransposon on host immunity. Given that the activation of retrotransposon likely contributes to inflammation in neurodegenerative disease and increases immunogenicity of cancer cells, our findings will potentially provide new perspectives to harness them for treating related diseases.