Each year vector-borne diseases afflict millions of people worldwide, impacting health care systems and economic resources. Contributing to the resurgence of many vector-borne diseases is the resistance to antimicrobials, pesticides and insecticides. In order to develop new counter-measures, we must identify new targets that disrupt the transmission cycle for these diseases. This effort is hindered by the lack of genetic tools and resources available to study the microbe-vector interactions. Our project is aimed at overcoming those obstacles by developing a new model system in which to identify genetic factors important for the interaction of Yersinia pestis (causative agent of plague) with its flea vector. Our model system employs Drosophila melanogaster, the fruit fly, as a surrogate for the flea. Drosophila has been used as a model to study innate immunity as wells as a variety of infectious diseases. We will couple the powerful genetic tools available for flies and Y. pestis with high throughput technologies to identify pathways that contribute to colonization of insects. This innovative approach will serve as a platform in future work that will investigate the molecular details of insect colonization using whole organisms, rather than simulative in vitro conditions. Importantly, our model system with its high throughput capabilities has the potential to be adapted to a drug discovery platform in order to identify compounds that disrupt the microbe-vector interaction for plague and other diseases.