The red flour beetle Tribolium castaneum has emerged as the genetically tractable model insect for population genetics, functional genomics, and evolutionary studies. This agricultural pest is notorious for its potential to severely damage stored products. T. castaneum has developed resistance to almost all insecticides. The reports of insecticide resistance from different parts of the world show that sustained insecticide usage has only aggravated the problem. As insecticides continue to be the mainstay of pest control programs, it is essential to identify the factors influencing insecticide resistance for implementing effective pest-management strategies. The development and progression of insecticide resistance in T. castaneum is thus an escalating global issue requiring immediate solutions. Several studies have investigated the multiple resistance mechanisms found in T. castaneum, such as reduced cuticular penetration, increased metabolic detoxification, and target-site insensitivity. The availability of Whole Genome Sequence and recent advances in Next Generation Sequencing technology has furthered a geneticist’s grasp of resistance study in Tribolium. The strategic containment of this organism calls for an in-depth understanding of resistance development. The review mainly focuses on different kinds of resistance mechanisms and genes mediating insecticide resistance. Also, it exhaustively explores the CYP450 gene superfamily in Tribolium to emphasize its role in governing resistance. The consolidated insights from this study will facilitate further research on identifying biological targets, thereby developing novel control strategies for effective insect control.