Covering: up to May 2006.

This Highlight provides an overview of the molecular logic employed in the formation and elaboration of pyrroles during natural product biosyntheses. The pyrrole ring, either in its unadorned form or as the pyrrole-2-carboxylate moiety commonly encountered in natural products, possesses many useful chemical and electronic features that are readily exploited in biological contexts. The ring itself is planar and electron rich, highly susceptible to electrophilic attack, capable of oxidation and able to participate in both π–π stacking and hydrogen-bonding interactions; the 2-carboxylate moiety provides a nucleophilic center for derivatization, hydrogen bonding and reaction with biological targets. The focus of this Highlight is primarily on the construction of pyrrole rings during secondary metabolite formation, and on their derivatization and incorporation into natural products. Overall biosynthetic strategies are discussed as well as relevant enzymology and mechanistic details.