Simple SummaryThe Colorado potato beetle is an insect pest known for the substantial damage it can cause on potato crops worldwide. Various strategies, including insecticides, have been deployed to limit its impact, with different levels of success. Insecticide resistance is often observed in this insect, and understanding the factors responsible for this adaptation is important towards the goal of mitigating this challenge. This review will thus highlight key targets associated with insecticide resistance in the Colorado potato beetle and present the potential of RNAi in modulating the susceptibility of this pest towards diverse compounds.AbstractThe Colorado potato beetle,Leptinotarsa decemlineataSay, is a potato pest that can cause important economic losses to the potato industry worldwide. Diverse strategies have been deployed to target this insect such as biological control, crop rotation, and a variety of insecticides. Regarding the latter, this pest has demonstrated impressive abilities to develop resistance against the compounds used to regulate its spread. Substantial work has been conducted to better characterize the molecular signatures underlying this resistance, with the overarching objective of leveraging this information for the development of novel approaches, including RNAi-based techniques, to limit the damage associated with this insect. This review first describes the various strategies utilized to controlL. decemlineataand highlights different examples of reported cases of resistances against insecticides for this insect. The molecular leads identified as potential players modulating insecticide resistance as well as the growing interest towards the use of RNAi aimed at these leads as part of novel means to control the impact ofL. decemlineataare described subsequently. Finally, select advantages and limitations of RNAi are addressed to better assess the potential of this technology in the broader context of insecticide resistance for pest management.