A diverse array of secondary metabolites in plants represents the process of coevolution between the plants and their natural enemies including herbivores and pathogens. For defense, plants produce many toxic compounds that harm other organisms. However, if the target of these compounds is a fundamental biological process then the producing plant may also be harmed. In such cases self-resistance strategies must coevolve with the biosynthetic pathway of toxic metabolites. In this review, we discuss the recent elucidation of the self-resistance mechanism of camptothecin (CPT)-producing plants. In this case the target protein of CPT, topoisomerase (Top) 1, has been mutated in order to overcome the toxicity of the compound. Similar mechanisms might also be used by other plants producing different toxic compounds which target fundamental metabolism.