DNA topoisomerase II inhibitors are among the most widely used anticancer agents. These drugs are potent inducers of DNA strand breaks and G2 arrest. However, topoisomerase II is not only a target for anti-cancer drugs but also part of the cellular response to different types of DNA damage. Topoisomerase II forms molecular complexes with important cell cycle regulators including the p53 oncogene suppressor, the BRCT-containing protein TopBP1, 14-3-3 epsilon and Cdc2 kinase. The association between topoisomerase II and Cdc2 kinase likely represents the earliest step in mitotic chromatin condensation. Therefore, regulation of the topoisomerase II/Cdc2 interaction could represent a novel mechanism to delay mitotic onset.