Identifying pathogenicity genes can be difficult because redundancy means that perturbing the function of a single pathogen gene often fails to result in a phenotype. This paper describes a method called insertional mutagenesis and depletion (iMAD), in which pathogenic Legionella pneumophila bacteria are first subject to mutagenesis and are then screened for their ability to grow in Drosophila cells that are depleted, by RNA interference, of different components of the secretory system. This screening revealed pathogen genes that target overlapping host pathways, allowing virulence factors with redundant roles to be identified and enabling the authors to dissect the complex network of host–pathogen interactions.