<p>The global decline of honey bee (<i>Apis mellifera</i> L.) populations is a significant concern due to their crucial role in pollination. This decline is largely attributed to various stressors, particularly agrochemical exposure which demonstrably reduces bee longevity and foraging efficiency. Bees possess a sophisticated three-phase detoxification system, involving key enzymes such as cytochrome P450 monooxygenases, glutathione-s-transferases, and carboxylesterases, to counter the detrimental effects of foreign substances (xenobiotics). However, the combined exposure to insecticides, fungicides, and other agrochemicals often leads to synergistic toxicity, overwhelming these detoxification pathways. Understanding the mechanisms of these synergistic interactions is crucial for comprehending their amplified impact. Research approaches range from basic methods like bioassays and enzyme activity studies to advanced methodologies such as transcriptomics, proteomics, and functional gene analyses, all aimed at elucidating the molecular basis of pesticide detoxification. Beyond enzymatic mechanisms, diet plays a pivotal role in modulating gene expression and enhancing bee resilience. Nutritional components found in pollen, propolis, honey, and various phytochemicals are vital in mitigating the risks posed by xenobiotics. This review focuses on several key areas: the differential pesticide sensitivity between susceptible and resistant bee populations, the enzymatic mechanisms underlying xenobiotic detoxification in bees, the processes driving xenobiotic synergy, and the importance of multifaceted approaches to investigate the molecular factors contributing to pesticide tolerance. Furthermore, it explores the influence of diet-dependent gene expression on detoxification pathways, offering valuable insights to improve bee resilience and support ongoing sustainability efforts.</p>