Bioinformatics approaches in the search for natural products are a combination of molecular and chemical techniques. Important criteria of molecular approaches include phylogenetic resolution and potential to a large-scale screening. Application of comparative genome sequence analysis is essential for a better understanding of the genetic and epigenetic components of different bacterial taxa. With the increased numbers of fully sequenced microbial genomes, including those of well-known bacterial producers of natural products, it has become clear that the genomic and metabolic capacity of these microorganisms is much higher than initially anticipated. This is due to the discovery of ‘silent’ or ‘cryptic’ secondary metabolite gene clusters that encode the production of additional, unidentified compounds. Bioinformatics tools for the construction of metabolic networks from genome sequence and information from the literature can be used to infer and describe natural products synthesis pathways and analyze the production machinery of bacterial producers. It is generally recognized, particularly in systems responsible for the synthesis of diverse antibiotics, that, for example, nonribosomal peptide synthesis occurs within a molecular complex composed of modules or subunits grouping peptide synthetase modules and associated enzymatic activities.