Drosophila melanogaster has proven to be a powerful genetic model to study human disease. Approximately 75% of human disease-associated genes have homologs in the fruit fly and regulatory pathways are highly conserved in Drosophila compared to humans. Drosophila is an established model organism for the study of genetics and developmental biology related to human disease and has also made a great contribution to epigenetic research. Many key factors that regulate chromatin condensation through effects on histone post-translational modifications were first discovered in genetic screens in Drosophila. Recently, the importance of chromatin regulators in cancer progression has been uncovered, leading to a rapid expansion in the knowledge on how perturbations of chromatin can result in the pathogenesis of human cancer. In this review, we provide examples of how Drosophila melanogaster has contributed to better understanding the detrimental effects of mutant forms of histones, called 'oncohistones', that are found in different human tumours.