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Covering: May 1966 up to January 2022 Entomopathogenic microorganisms have potential for biological control of insect pests. Their main secondary metabolites include polyketides, nonribosomal peptides, and polyketide–nonribosomal peptide (PK–NRP) hybrids. Among these secondary metabolites, polyketides have mainly been studied for structural identification, pathway engineering, and for their contributions to medicine. However, little is known about the function of polyketides in insect virulence. This review focuses on the role of bacterial and fungal polyketides, as well as PK–NRP hybrids in insect infection and killing. We also discuss gene distribution and evolutional relationships among different microbial species. Further, the role of microbial polyketides and the hybrids in modulating insect–microbial symbiosis is also explored. Understanding the mechanisms of polyketides in insect pathogenesis, how compounds moderate the host–fungus interaction, and the distribution of PKS genes across different fungi and bacteria will facilitate the discovery and development of novel polyketide-derived bio-insecticides. [ABSTRACT FROM AUTHOR]