The present review discusses recent evidence on the mechanisms of formation of structural and numerical chromosome aberrations by anti-topoisomerase drugs. Among “cleavable complex”poisoning drugs, DNA topoisomerase II inhibitors induce DNA double strand breaks that lead to chromosomal aberrations independently of the phase of the cell cycle in which the treatment has been performed. Inhibitors of DNA topoisomerase I induce DNA single strand breaks that are transformed in DSB when the trapped “cleavable complex” collides with the replication fork, producing chromatid-type aberrations. Recently, ongoing chromosome condensation and RNA transcription have been shown to play a crucial role in the formation of chromatid-type aberrations by topoisomerase I poisons for treatments in the G2 phase of the cell cycle. Mutations of single genes are also induced by anti-topoisomerase drugs. These consist mostly of deletions, duplications and insertions and are often localized at the topoisomerase cleavable sites. This suggests that alterations at the chromatin level may be responsible for inactivation of gene function after topoisomerase inhibitors. Anti-topoisomerase drugs promote also numerical chromosome aberrations as DNA topoisomerases are involved in chromosome condensation and segregation at mitosis. Polyploid cells are induced as a consequence of the total inhibition of sister chromatid separation before anaphase and aneuploid cells may arise when sister chromatid separation is defective. Gene mutations, chromosomal aberrations and aneuploidy may influence the stability of the genome further producing structural aand numerical aberrations at successive cell cycle divisions. Knowledge of the mechanisms producing gene mutations, chromosome aberrations and genomic instability after drugs interacting with topoisomerases is essential for developing effective therapeutical approaches.