Nonribosomal peptide synthetases (NRPSs) are true macromolecular machines, having modular assembly-line logic, a complex catalytic cycle, moving parts and many active sites. NRPS peptide products include classics therapeutics (penicillin, cyclosporin, and modern billion-dollar antibiotics (daptomycin) and anti-cancer agents (dactinomycin). We have performed structural and functional analyses of components of the NRPS systems responsible for the syntheses of the antibiotic gramicidin, the siderophore bacillibactin and the anti-algae bacillamide. I will discuss results from these studies and the insight they provide into the superdomain and supermodular architecture, conformational changes and mechanisms of tailoring NRPSs use to synthesize their important bio-active products.