Cancer is a genetic disease that involves the gradual accumulation of mutations. Human tumours are genetically unstable. However, the current knowledge about the origins and implications of genomic instability in this disease is limited. Understanding the biology of cancer requires the use of animal models. Here, we review relevant studies addressing the implications of genomic instability in cancer by using the fruit fly, Drosophila melanogaster, as a model system. We discuss how this invertebrate has helped us to expand the current knowledge about the mechanisms involved in genomic instability and how this hallmark of cancer influences disease progression.