Our driving interest is to discover the spectrum of cellular factors at the virus-host interface and to elucidate the mechanisms by which pathogens subvert this cellular machinery while evading recognition. We use a combination of functional genomics coupled with cutting-edge molecular approaches to define both the players and mechanisms involved. We have performed a large number of genome-wide RNAi screens and these data have revealed fundamental insights into the plethora of pathways engaged to block infection. Furthermore, we have compared and contrasted host factor dependencies across diverse human arthropod-borne viruses exploring genes and pathways active in both insects and humans. We use the model organism Drosophila for its powerful genetic tools and focus on conserved genes that play parallel roles in both vectors and humans. Using this system we have identified complex mechanisms involved in viral RNA recognition and restriction, roles for the microbiota and microbial metabolites in the control of enteric infection as well as new innate signaling pathways that impact infection in neurons. We will discuss our new findings on the pathways and players involved in virus-host interactions.