<jats:p> Lantibiotics are ribosomally synthesized oligopeptide antibiotics that contain lanthionine bridges derived by the posttranslational modification of amino acid residues. Here, we describe the cinnamycin biosynthetic gene cluster ( <jats:italic>cin</jats:italic> ) from <jats:italic>Streptomyces cinnamoneus cinnamoneus</jats:italic> DSM 40005, the first, to our knowledge, lantibiotic gene cluster from a high G+C bacterium to be cloned and sequenced. The <jats:italic>cin</jats:italic> cluster contains many genes not found in lantibiotic clusters from low G+C Gram-positive bacteria, including a <jats:italic>Streptomyces</jats:italic> antibiotic regulatory protein regulatory gene, and lacks others found in such clusters, such as a LanT-type transporter and a LanP-type protease. Transfer of the <jats:italic>cin</jats:italic> cluster to <jats:italic>Streptomyces lividans</jats:italic> resulted in heterologous production of cinnamycin. Furthermore, modification of the cinnamycin structural gene ( <jats:italic>cinA</jats:italic> ) led to production of two naturally occurring lantibiotics, duramycin and duramycin B, closely resembling cinnamycin, whereas attempts to make a more widely diverged derivative, duramycin C, failed to generate biologically active material. These results provide a basis for future attempts to construct extensive libraries of cinnamycin variants.