Pro‐insecticides have been a significant part of the insecticide market for decades. Bioactivation of such compounds is generally an enzyme‐controlled process, in which the target insect metabolizes the pro‐form into an active compound. This approach has several potential advantages, including improved bio‐kinetic properties and safety profiles of the pro‐insecticide relative to the active form. A less common advantage of pro‐insecticides is increased activity on metabolically resistant strains. Specific cases in which a pro‐insecticide demonstrates negative cross‐resistance (NCR) on a metabolically resistant strain due to increased bioactivation of the pro‐insecticide have been noted sporadically over the past 50+ years but have not been reviewed before. The purpose of this mini‐review is to catalog the cases in which a pro‐insecticide demonstrated improved activity on an insect strain resistant to a second insecticide via a metabolic mechanism. Cases are relatively rare, but where it does occur the mechanism of NCR is generally recognized as being due to the increased metabolic activity of the resistant strain. These observations can provide learnings with potential application for resistance management if the correct pro‐insecticide is selected for a resistant strain which is better able to bioactivate it. A better understanding of the bioactivation of pro‐insecticides by resistant insects could also aid in insecticide discovery, potentially leading to improved pro‐insecticide design. © 2021 Society of Chemical Industry Pro‐insecticides are bioactivated using many of the same mechanisms which impart metabolic resistance. Can pro‐insecticides therefore be utilized or designed to have a natural advantage in control of metabolically resistant strains?