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.