Polyketides are one of the largest and most structurally diverse classes of naturally occurring compounds, ranging from simple aromatic metabolites to complex macrocyclic lactones. Fungi and filamentous bacteria, particularly the actinomycetes, are major sources of polycyclic aromatic structures, which include many clinically important antibiotics and other useful metabolites. These fused‐ring polyketides are formed by the action of polyketide synthases (PKSs), which catalyse the assembly, folding and cross‐linking of poly‐β‐ketoacyl intermediates. In view of the taxonomic gulf between the eukaryotic fungi and prokaryotic bacteria, it is not surprising that they are rarely found to produce structurally identical fused‐ring metabolites. A review of [13C2]acetate incorporation data has revealed consistent differences in the reported cyclisation patterns, which require regiospecifically distinct cross‐linking of otherwise identical linear polyketide precursors. This observation provides the basis for a structural and biosynthetic classification of microbial fused‐ring polyketides, which has a number of useful ramifications.