DNA topoisomerase II is an essential enzyme that regulates DNA topology to facilitate critical cellular processes such as transcription, replication and cell division. Topoisomerase II creates double-stranded DNA breaks and passes an intact double helix through the break in order to alleviate supercoiling and untangle interlinked DNA helices. Topoisomerase II accomplishes this by cleaving the DNA four base pairs apart on opposite strands generating a transient, enzyme-linked double-stranded break. These transient enzyme-DNA complexes, termed cleavage complexes, pose a threat to genomic integrity with the possibility of permanent double- and single-stranded breaks. A number of compounds target topoisomerase II and take advantage of this cellular threat for the treatment of cancer and bacterial infections. Unfortunately, some of these agents lead to translocations, which have been associated with the development of specific types of leukemias. Most anticancer agents use a more traditional interfacial mechanism to physically block ligation of the cleaved DNA. Accumulation of cleavage complexes presents a physical obstruction on the genetic material, which can lead to permanent strand breaks when DNA tracking systems collide with the cleavage complexes. However, a growing class of compounds causes an increase in DNA cleavage through a covalent mechanism. Formerly referred to as redox poisons, these covalent poisons share many common characteristics including covalent adduction to the enzyme. These compounds come from a number of sources including dietary and plant-derived, industrial chemicals, and drug metabolites. In this review, we will focus on these covalent poisons of topoisomerase II.