Homocamptothecins (hCPTs) represent a new generation of antitumor agents targeting DNA topoisomerase I. The expanded seven-membered lactone E-ring that characterizes hCPTs enhances the plasma stability of the drug and reinforces the inhibition of topoisomerase I compared with conventional six-membered CPTs. hCPTs are more efficient than the CPTs at promoting cleavage at T/G sites and induce additional cleavage at C/G sites. Compound BN80765 and its difluoro analogue diflomotecan (DN80915) are potent cytotoxic agents and efficiently induce apoptosis in tumor cells. They display strong antiproliferative activities against specific tumor types. Diflomotecan is remarkably efficient at inhibiting the growth of human colon cancer cells in vivo and, administered orally, it also shows superior activities against human prostate cancers compared with the benchmark products topotecan (TPT) and irinotecan (IRT). Diflomotecan has entered phase I clinical testing and antitumor activity has been observed in patients. This 9,10-difluoro-hCPTs derivative is one of the most promising new members of the 'tecan' family. This review summarizes the recent discoveries in the topoisomerase I field and presents the different camptothecin (CPT) analogues currently evaluated as anticancer agents. The specific properties of hCPTs are highlighted.