The bacterial kingdom provides a major source of antimicrobials that can either be directly applied or used as scaffolds to further improve their functionality in the host. The rapidly increasing amount of bacterial genomic, metabolomic and transcriptomic data offers unique opportunities to apply a variety of approaches to mine for existing and novel antimicrobials. Here, we discuss several powerful mining approaches to identify novel molecules with antimicrobial activity across structurally diverse natural products, including ribosomally synthesized and posttranslationally modified peptides, nonribosomal peptides and polyketides. We not only discuss the direct mining of genomes based on identification of biosynthetic gene clusters, but also describe more advanced and integrative approaches in ecology-based mining, functionality-based mining and mode-of-action-based mining. These efforts are likely to accelerate the discovery and development of novel antimicrobial drugs.