Type II DNA topoisomerases have the ability to generate a transient DNA double-strand break through which a second duplex can be passed; an activity essential for DNA decatenation and unknotting. Topoisomerase poisons stabilize the normally transient topoisomerase-induced DSBs and are potent and widely used anticancer drugs. However, their use is associated with therapy-related secondary leukemia, often bearing 11q23 translocations involving the <em>MLL </em>gene. We will explain recent discoveries in the fields of topoisomerase biology and transcription that have consequences for our understanding of the etiology of leukemia, especially therapy-related secondary leukemia and describe how these findings may help minimize the occurrence of these neoplasias.