The catalytic activities of topoisomerase II are responsible primarily for solving the complex topological problems that arise from cellular processes such as DNA replication, transcription and chromosome segregation; however, topoisomerase II may also play a crucial structural role in the chromosome scaffold. Cell-cycle-regulated phosphorylation might be the key to these diverse functions. Phosphorylation of topoisomerase II might trigger the enzymatic activities essential for mitosis and promote interactions with specialized DNA sequences and other protein components of the eukaryotic chromosome to ensure the proper establishment and maintenance of chromatin architecture and function.