The striking phenomenon of endoreduplication has long attracted attention from cytogeneticists and researchers into cell cycle enzymology and dynamics alike. Because of the variety of agents able to induce endoreduplication and the various cell types where it has been described, until now no clear or unique mechanism of induction of this phenomenon, rare in animals but otherwise quite common in plants, has been proposed. Recent years, however, have witnessed the unfolding of a number of essential physiological roles for DNA topoisomerase II, with special emphasis on its major role in mitotic chromosome segregation after DNA replication. In spite of the lack of mammalian mutants defective in topoisomerase II as compared with yeast, experiments with inhibitors of the enzyme have supported the hypothesis that this crucial untangling of daughter DNA molecules by passing an intact helix through a transient double-stranded break carried out by the enzyme, when it fails, leads to aberrant mitosis that results in endoreduplication, polyploidy and eventually cell death. Anticancer drugs that interfere with topoisomerase II can be classified into two groups. The classical poisons act by stabilizing the enzyme in the so-called cleavable complex and result in DNA damage, which represents a problem in the study of endoreduplication. The true catalytic inhibitors, which are not cleavable complex stabilizers, allow us to use doses efficient in the induction of endoreduplication while eliminating high levels of DNA and chromosome damage. This review will discuss the basic and applied aspects of this as yet scarcely explored field.