Progress in our understanding of the complex signaling events driving human cancer would have been unimaginably slow without discoveries from Drosophila genetic studies. Significantly, many of the signaling pathways now synonymous with cancer biology were first identified as a result of elegant screens for genes fundamental to metazoan development. Indeed the name given to many core cancer-signaling cascades tells of their history as developmental patterning regulators in flies—e.g. Wingless (Wnt), Notch and Hippo. Moreover, astonishing insight has been gained into these complex signaling networks, and many other classic oncogenic signaling networks (e.g. EGFR/RAS/RAF/ERK, InR/PI3K/AKT/TOR), using sophisticated fly genetics. Of course if we are to understand how these signaling pathways drive cancer, we must determine the downstream program(s) of gene expression activated to promote the cell and tissue over growth fundamental to cancer. Here we discuss one commonality between each of these pathways: they are all implicated as upstream activators of the highly conserved MYC oncogene and transcription factor. MYC can drive all aspects of cell growth and cell cycle progression during animal development. MYC is estimated to be dysregulated in over 50% of all cancers, underscoring the importance of elucidating the signals activating MYC. We also discuss the FUBP1/FIR/FUSE system, which acts as a ‘cruise control’ on the MYC promoter to control RNA Polymerase II pausing and, therefore, MYC transcription in response to the developmental signaling environment. Importantly, the striking conservation between humans and flies within these major axes of MYC regulation has made Drosophila an extremely valuable model organism for cancer research. We therefore discuss how Drosophila studies have helped determine the validity of signaling pathways regulating MYC in vivo using sophisticated genetics, and continue to provide novel insight into cancer biology.