Innate Immunity in the Fly Gut: Drosophila melanogaster is an important model system to study innate immunity, being both easy to manipulate and lacking an adaptive immune system. In order to identify genes that regulate innate immunity, Cronin et al. (p. 340 ; published online 11 June) performed an RNA interference screen on flies infected with the oral bacterial pathogen, Serratia marcescens . Genes involved in intestinal immunity and regulation of hemocytes, macrophage-like cells critical for phagocytosis and killing of the bacteria, were identified. Several hundred genes conferred either enhanced susceptibility or resistance to bacterial infection. Furthermore, the JAK/STAT signaling pathway was activated in intestinal stem cells after bacterial infection, resulting in enhanced susceptibility to infection, most likely through regulation of intestinal stem cell homeostasis.