Historically, nature has provided the source for the majority of the drugs in use today. This owes in large part to their structural complexity and clinical specificity. However, only a small percentage of known microbial secondary metabolites have been tested as natural-product drugs. Natural-product programs need to become more efficient, starting with the collection of environmental samples, selection of strains, metabolic expression, genetic exploitation, sample preparation and chemical dereplication. A renaissance of natural products-based drug discovery is coming because of the trend of combining the power of diversified but low-redundancy natural products with systems biology and novel assays. This review will focus on integrated approaches for diversifying microbial naturalproduct strains and extract libraries, while decreasing genetic and chemical redundancy. Increasing the quality and quantity of different chemical compounds tested in diverse biological systems should increase the chances of finding new leads for therapeutic agents.