Arthropods have the capacity to evolve resistance to insecticides and insecticidal traits in genetically modified crops. Resistance development among Lepidoptera is a common phenomenon, and a repertoire of resistance mechanisms to various Cry toxins have been identified from laboratory, greenhouse, and field studies in this insect order. Elucidation of such resistance mechanisms is crucial for developing IRM (insect resistance management) strategies to ensure sustainable use of genetically modified crops. This mini review provides a comprehensive overview of mechanisms of resistance that have been reported for lepidopteran pests. This study demonstrated that resistance mechanisms are highly complex, and the most common mechanism of resistance is altered binding sites. It is yet to be established whether all these altered binding sites are regulated by an MAPK signaling pathway, which might suggest a universal mechanism of resistance in lepidopterans.