It is occasionally observed that common sporadic diseases have rare familial counterparts in which mutations at a single locus result in a similar disorder exhibiting simple Mendelian inheritance. Such an observation is often sufficient justification for the creation of a disease model in the fly. Whether the system is based on the over-expression of a toxic variant of a human protein or requires the loss of function of an orthologous fly gene, the consequent phenotypes can be used to understand pathogenesis through the discovery of genetic modifiers. Such genetic screening can be completed rapidly in the fly and in this review we outline how libraries of mutants are generated and how consequent changes in disease-related phenotypes are assessed. The bioinformatic approaches to processing the copious amounts of data so generated are also presented. The next phase of fly modelling will tackle the challenges of complex diseases in which many genes are associated with risk in the human. There is growing interest in the use of interactomics and epigenetics to provide proteome- and genome-scale descriptions of the regulatory dysfunction that results in disease.