Synergists have been used commercially for about 50 years and have contributed significantly to improve the efficacy of insecticides, particularly when problems of resistance have arisen. In the current article we review the nature, mode of action, role in resistance management, natural occurrence, and significance in research of insecticide synergists. These natural or synthetic chemicals, which increase the lethality and effectiveness of currently available insecticides, are by themselves considered nontoxic. The mode of action of the majority of synergists is to block the metabolic systems that would otherwise break down insecticide molecules. They interfere with the detoxication of insecticides through their action on poly‐substrate monooxygenases (PSMOs) and other enzyme systems.