Polyketides are a class of natural products isolated from a wide variety of species. In bacteria, diverse skeletons of polyketides lead to different biological functions, including anti-bacteria, anti-fungi, anti-tumor and immunomodulation. Polyketide synthases (PKSs) are responsible for the biosynthesis of polyketides through successive Claisen condensations of short-chain fatty acids. PKSs are classified into type Ⅰ, type Ⅱ and type Ⅲ, producing different polyketide scaffolds. Bacterial PKSs often hybridize with other biosynthetic enzymes to form PKS hybrids, such as PKS-NRPS or PKS-Ripps, exhibiting more complicated and unique structures. Additionally, different types of PKS can also form inter-PKS hybrids to generate different skeletons. In this review, we summarize recent advances in the structures and biosynthetic mechanisms of bacterial inter-PKS hybrids, including type Ⅰ PKS internal hybrids, type Ⅰ/Ⅱ PKS hybrids and type Ⅰ/Ⅲ PKS hybrids with the following context: (1) In atypical type Ⅰ PKSs, some modules may iteratively catalyze multiple rounds of carbon chain growth, resulting in iterative/non-iterative PKS hybrids; (2) trans-AT PKS and cis-AT PKS can also form PKS hybrids, and the synthesis of kirromycin is a representative example; (3) Type Ⅰ PKSs synthesize unique starter units for type Ⅱ PKSs to produce polyketide scaffolds with the alkyl groups; (4) Type Ⅲ PKSs can condense malonyl-CoA to form different aromatic acids through multiple tailoring steps, and the aromatic acids subsequently act as the starter unit or extender unit into the type Ⅰ PKS assembly line. By elucidating the biosynthetic gene clusters and biosynthetic pathways of inter-PKS hybrids, the reconstructions of inter-PKS hybrids for synthesizing pharmaceutically important analogues are possible. This review also comments the discovery of new inter-PKS hybrids and the engineering of their biosynthetic machineries, to gain more insights into their biosynthetic potential for the production of diverse molecules. By comparing the biosynthetic mechanisms of PKS and discussing the progress of engineering modifications, we prospect a variety of potential inter-PKS hybrid models, highlight the direction for the genome mining of novel polyketides, and provide insights for the engineering modifications of PKS. Through further in-depth and systematic studies on various inter-PKS hybrids in bacteria, it is expected to reveal more natural conundrums, generating a large number of new natural products through adaptive transformation for the research and development of microbial drugs.