The AIDS pandemic has been a major challenge to global health for nearly three decades. According to current estimates, over 34 million people are still living with HIV worldwide. Although the introduction of antiretroviral therapy (HAART) has considerably reduced HIV-related mortality rates, HAART fails to achieve complete viral clearance and still raises drug toxicity and resistance issues. Besides advances in the treatment of HIV infection, numerous efforts have also been made on HIV prevention. However, despite extensive research, no prophylactic HIV vaccine has emerged to date. Consequently, topical microbicides have recently been improved as a solution to moderate HIV transmission but the clinical trials were globally unsatisfactory. As a consequence, innovative approaches to identify new anti-HIV molecules are critical.Host defence peptides (HDPs) constitute an exciting class of drug candidates, especially because they are unlikely to induce drug resistance. HDPs constitute important components of the innate host defence against a broad spectrum of pathogens. To date, several natural biologically active HIV inhibitors have been characterized. However, systematic screens for naturally occurring anti-HIV peptides has been a major failure due to technical issues but also to a limited accessibility of fluids, tissues or organelles enriched in HDPs. Secretory granules are unique organelles in which secretory products are stored upon secretion. Secretory granules of neuroendocrine cells are particularly enriched in HDPs and therefore constitute an excellent model to screen new anti-HIV compounds. Here, we propose an innovative approach to identify new potent anti-HIV peptides, using the secretory granules of neuroendocrine cells as a model. Our long-term goal is to characterize the lead molecules as a prerequisite to the development of new anti-HIV components that can be used as an alternative to HAART or for the development of a new HIV microbicide.