The soil actinomycetes have been important sources of antibiotics, but were nearly abandoned in recent years in favor of high-throughput target-based screening of chemical libraries. The latter approach has not been productive, so it is time to reinvigorate the discovery of new antibiotics from a proven source. Recent progress has been made on antibiotic discovery from actinomycetes by using high-throughput fermentation, isolation of marine actinomycetes, mining genomes for cryptic pathways, and combinatorial biosynthesis to generate new secondary metabolites related to existing pharmacophores.