Transformation and metastasis are complex processes that depend on integration of effects from multiple mutations. Modeling this complexity requires manipulating multiple genes in particular sub-populations of cells in vivo. This is technically challenging in mammalian model systems and has limited the rate of progress in understanding the effects of the complex aberrations present in cancer cells. In contrast, powerful genetic methods in the fruit fly Drosophila allow efficient generation and analysis of complex genotypes in defined cell populations. These methods are already fruitful in exploring the interactions among cancer mutations, and between cell populations that mimic the tumor microenvironment. In this issue of Oncogene, Willecke et al. (2011) describe the implementation of a novel genetic screen in Drosophila to identify genes required for tumor growth in vivo. This report illustrates the power of using Drosophila to perform systematic genome-wide genetic screens in complex genetic backgrounds and for the resulting data to inform our understanding of transformation and metastasis in human systems.