Topotecan and irinotecan are both derivatives of the plant alkaloid camptothecin [1]. They are widely used for the treatment of solid tumors including colon, lung and ovarian cancers as well as pediatric tumors. Since their FDA approval almost 20 years ago, they have remained the only marketed topoisomerase I (TOP1) inhibitors [2]. This situation is unique in the anticancer armamentarium and is primarily related to the fact that pharmaceutical companies turned to the discovery of protein kinase inhibitors (often referred to as “targeted therapies”) shortly before the clinical approval of topotecan and irinotecan. Yet, camptothecins can be nominated “targeted therapies” as they only target TOP1, and crystal structures demonstrate that only the active natural stereoisomers (20-S) of the camptothecins (see top right of the Figure 1) bind to the TOP1-DNA interface (scheme in the middle of the Figure 1), stacking with the base pairs that flank the DNA cleavage site generated by TOP1 and forming a network of hydrogen bonds with amino acid residues of the TOP1 catalytic pocket [3]. This finding led to the concept of interfacial inhibition, a molecular mechanism of action for a wide variety of natural products including TOP2 inhibitors, rapamycin, tubulin inhibitors and anesthetic drugs [3]. Binding of a single molecule of a camptothecin or indenoisoquinoline [4] traps the TOP1-DNA complex by blocking the religation of the broken DNA and the release of TOP1, which remains covalently attached to the 3’-end of the break that TOP1 made to relax DNA. As a result, camptothecins and indenoisoquinolines act by producing TOP1 cleavage complexes (TOP1cc).