Covering: up to August 2020The dramatic increase in the identification of dimeric natural products generated by microorganisms and plants has played a significant role in drug discovery. The biosynthetic pathways of these products feature inherent dimerization reactions, which are valuable for biosynthetic applications and chemical transformations. The extraordinary mechanisms of the dimerization of secondary metabolites should advance our understanding of the uncommon chemical rules for natural product biosynthesis, which will, in turn, accelerate the discovery of dimeric reactions and molecules in nature and provide promising strategies for the total synthesis of natural products through dimerization. This review focuses on the enzymes involved in the dimerization in the biosynthetic pathway of microbial natural products, with an emphasis on cytochrome P450s, laccases, and intermolecular [4 + 2] cyclases, along with other atypical enzymes. The identification, characterization, and catalytic landscapes of these enzymes are also introduced.