Certain biorational chemical agents used against insect pests impact essential stages or processes in insect life cycles when applied for pest management. Development of resistance to these agents, while involving maintenance of the natural role of the chemical agent, frequently requires the evolution of a new chemical structure by the resistant organism. When considering the process of resistance development, one could theoretically consider biorational structural determination rather than the less predictable or feasible generation of a novel replacement insecticide. At first consideration, this process might exclude toxicants such as typical pest control agents and rather be a phenomenon reserved principally for signalling processes such as are fulfilled by pheromones and other semiochemicals. However, because there is a unique co-evolutionary relationship between chemical defence and the physiology of the antagonistic organism, this process can be further explored for potential to overcome resistance to toxins. Given further consideration, newly evolved chemical defences may rationally provide options for new resistance-defeating chemistry. This review therefore discusses the potential for overcoming insecticide resistance through targeted application of this approach. Potential for use of a similar approach to counteract fungicide and herbicide resistance is also considered. Furthermore, the possible applications of this approach to address drug or pharmaceutic resistance are also considered.