Post-translational modifications of histones play a critical role in gene expression control. Ultimately, cancer is a disease of aberrant gene expression. Accordingly, several histone-modifying enzymes have been described as proto-oncogenes or tumor suppressors. Recent reports, including one from Shema and colleagues (pp. 2664- 2676) in the October 1, 2008, issue of Genes and Development, indicate that deregulation of histone H2B monoubiquitination may contribute to cancer development.