Chemotherapeutic agents that target topoisomerase I and II set into motion a series of biochemical changes that culminate in cell death, but only under some conditions. The realization that stabilization of covalent topoisomerase-DNA complexes is not sufficient to insure cell death has prompted investigators to examine various aspects of the drug-induced death process itself. Several discrete steps along this pathway have been identified, including (a) the processing of stabilized cleavage complexes into frank DNA strand breaks; (b) sensing of the DNA damage, leading to activation of stress-associated signaling pathways and cell cycle arrest; and (c) activation of a preexisting group of enzymes and enzyme precursors, typified by the cysteine-dependent aspartate-directed proteases (caspases), that catalyze the relatively orderly biochemical cascade of terminal events known as apoptosis. The present review discusses the evidence that these steps occur after treatment with etoposide or camptothecin, the two prototypic topoisomerase poisons that are commonly studied. As in any emerging area, a large number of questions remain to be answered about the process of cell death induced by topoisomerase-directed drugs.