<p>Natural products (NPs) from bacteria and fungi have contributed substantially to human health and life. They have particularly attracted attention due to their intriguing bioactivity and complex structures. Biosynthetic gene clusters (BGCs), which encode biosynthetic enzymes to catalyze the biochemical cascade reactions, are responsible for the biosynthesis of NPs. Canonical BGCs have apparent core enzymes to produce several types of NPs according to their disparate skeleton structures. However, recent studies have discovered some BGCs that do not have prominent canonical core enzymes to perform the backbone-defining transformation of NPs, but produce more structurally diverse NPs with intriguing biosynthetic logic. Herein, this type of BGCs is classified as unusual gene clusters (uGCs). In this review, we summarize advances on bacterial and fungal NPs produced from uGCs, the featuring enzymes to produce these NPs, as well as the key distinct biosynthetic steps. Further studies on these uGCs will greatly enrich the genetic and chemical repertoire of microbial NPs.</p>