A metabolome‐guided screening approach in the novel myxobacterium Corallococcus sp. MCy9072 resulted in the isolation of the unprecedented natural product myxofacycline A, which features a rare isoxazole substructure. Identification and genomic investigation of additional producers alongside targeted gene inactivation experiments and heterologous expression of the corresponding biosynthetic gene cluster in the host Myxococcus xanthus DK1622 confirmed a noncanonical megaenzyme complex as the biosynthetic origin of myxofacycline A. Induced expression of the respective genes led to significantly increased production titers enabling the identification of six further members of the myxofacycline natural product family. Whereas myxofacyclines A–D display an isoxazole substructure, intriguingly myxofacyclines E and F were found to contain 4‐pyrimidinole, a heterocycle unprecedented in natural products. Lastly, myxofacycline G features another rare 1,2‐dihydropyrol‐3‐one moiety. In addition to a full structure elucidation, we report the underlying biosynthetic machinery and present a rationale for the formation of all myxofacyclines. Unexpectedly, an extraordinary polyketide synthase‐nonribosomal peptide synthetase hybrid was found to produce all three types of heterocycle in these natural products. Discovering the natural route to “synthetic” heterocycles: Myxofacyclines are natural products isolated from myxobacteria. Myxofacyclines A–D display an isoxazole substructure, myxofacyclines E and F contain 4‐pyrimidinole, and myxofacycline G features another rare 1,2‐dihydropyrol‐3‐one moiety. The isoxazole, 4‐pyrimidinole or 1,2‐dihydropyrrol‐3‐one heterocycle in the myxofacyclines and the underlying biosynthesis are rarely described in natural products. Isolation, structure elucidation, mutagenesis of the producer strain and heterologous expression of the identified biosynthetic genes are presented.