A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effective when tested as a continuous exposure as compared with a 1-h exposure. The dose-limiting toxicities were different for all three of the agents, with neutropenia and thrombocytopenia being dose-limiting for topotecan; diarrhea, for CPT-11; and hepatotoxicity, for intoplicine. In these phase I studies a number of marginal responses were noted with topotecan; partial and marginal responses, with CPT-11 (particularly in patients with colon cancer); and no response, with intoplicine. The detailed pharmacology of all three agents documented a very short half-life for topotecan, an intermediate half-life for CPT-11, and a prolonged half-life for intoplicine. Based on our experience to date, these compounds (particularly CPT-11) have promise as useful additions to our tremendous therapeutic armamentarium.