Low‐molecular‐weight (LMW) thiols are extensively involved in the maintenance of cellular redox potentials and the protection of cells from a variety of reactive chemical and electrophilic species. However, we recently found that the metabolic coupling of two LMW thiols – mycothiol (MSH) and ergothioneine (EGT) – programs the biosynthesis of the anti‐infective agent lincomycin A. Remarkably, such a constructive role of the thiols in the biosynthesis of natural products has so far received relatively little attention. We speculate that the (...) unusual thiol EGT might function as a chiral thiolation carrier (for modification) and a novel activator (for glycosylation) of sugar. Additionally, we examine recent evidence for LMW thiols (MSH and others) as sulfur donors of sulfur‐containing natural products. Clearly, the LMW thiols have more diverse activities beyond cell protection, and more attention should be paid to the correlation of their functions with thiol‐dependent enzymes. (shrink)