he past decade has seen an upsurge in the available genomic information with about 800 fully sequenced bacterial genomes and around 700 unfinished genomes as of August 2009. This explosion of genomic information has provided unparalleled new insights into the genetic capacity of organisms to generate secondary metabolites 1 , including a rapid rise in the discovery of natural products that are ribosomally synthesized and post-translationally modified 2-13 . These tailoring processes release the peptides from the structural and functional constraints imposed on natural ribosomal peptides, while at the same time restricting conformational flexibility to allow better target recognition and increase metabolic and chemical stability. For the vast majority of natural products of ribosomal origin, the initial precursor peptide is much larger than the final product. These precursors typically contain N-terminal leader peptides, and in some cases, C-terminal extensions that are removed in the last step of the maturation process. Interestingly, a recent comprehensive analysis of the structural motifs generated using these pathways concluded that the types of structures accessible through the ribosomal route are remarkably similar to those produced via nonribosomal biosynthesis 14 . This review will discuss the currently available information regarding the roles of these leader peptides as well as the prospects that leader peptide-directed biosynthesis (LDB) offers for natural product engineering.