Actinomycete bacteria, such as S. coelicolor, have been a singularly rich source of bioactive molecules for the pharmaceutical and agricultural industries. Typically, "classical strain improvement" programs have been used to generate industrial strains of bacteria that produce high yields of commercially important natural products. However, the strategy is time-consuming and provides no information about overproduction mechanisms that can be used for rational engineering purposes. In this work, a forward engineering approach involving genome shuffling is being used to generate a new strain of S. coelicolor that produces 10x-100x actinorhodin antibiotic yields compared to the parental strain. Transposon mutagenesis was used to allow rapid identification of mutations causing overproduction. The recently sequenced S. coelicolor genome allows application of genomic technologies to the high-producing strain. Ten thousand transposon Tn4560 S. coelicolor mutagens have been generated, grown and screened in a high-throughput manner. Characterization of these mutants provides insights into S. coelicolor growth and antibiotic production behavior. The highest actinorhodin producers of these mutants will be recombined through genome shuffling to obtain multiple mutations per cell line. These progeny will be screened for the highest producers, reshuffled and screened again to generate the final super-overproducer. Creating this fundamentally new and potentially general way to produce large quantities of natural products such as actinorhodin will open new avenues for how polyketides are synthesized and used in research and commercial settings.