Many genetic tools are available to address the mechanisms of pathogen action in Drosophila. These include comprehensive genetic screens, or genome-wide RNAi screens, in cell lines and intact flies that can identify host pathways required to defend against pathogens. Reciprocally, it is also possible to search for pathogen-encoded factors that are required for virulence in flies. In vivo studies in flies are greatly facilitated by the ability to direct expression of transgenes encoding host or pathogen proteins in specific cell types using the GAL4-UAS transactivation system (Brand and Perrimon, 1993) or the new independently acting LexA system, which allows for combinatorial expression of genes in distinct or overlapping patterns (Yagi et al., 2010; Pfeiffer et al., 2010) . Moreover, it is possible to perform epistasis experiments using combinations of dominant and recessive mutations (or mutants with opposing phenotypes) in a given pathway to determine the sequence in which genes act in that pathway. These versatile tools, combined with the rapid Drosophila life cycle, allow detailed genetic analysis of virulence factors that act on tissues or organs; such experiments would be much more difficult to conduct in vivo in mammalian systems.