Following the realisation that DNA topoisomerase I is a useful therapeutic target to be exploited for the design of potential inhibitors, topoisomerase I inhibitors now represent an established class of effective agents. In spite of intense efforts in the field, only camptothecins have a clinical relevance. Several options in chemical manipulation of natural camptothecin have been explored to overcome the major drawbacks of the drug, which include water insolubility, lactone instability, reversibility of the drug-target interaction and drug resistance. Several analogues are currently in clinical development, including water soluble camptothecins, lipophilic camptothecins and polymer-bound camptothecins. The therapeutic advantages of novel camptothecins over the two analogues (topotecan and irinotecan) approved for clinical use remain to be defined. This article is an overview of the relevant features of the analogues that are undergoing clinical development.