This presentation provides a brief overview of the remarkable chemical diversity we have encountered while exploring natural products produced from bacteria and fungi isolated from a wide array of microbiomes, including marine fish gastrointestinal tracts, wasp and termite nests, mangrove muds, > 10,000 soils samples sourced from 1,000s of Australian backyards as part of a nationwide citizen science initiative “Soils for Science”, and even human faecal waters! By touching on a few case studies where we have demonstrated that natural products can inhibit drug efflux, combat infectious diseases including tuberculosis (humans) and helminths (animals), and present as promising new pharmacophores for the management of pain and inflammatory bowel diseases – as well as some pivotal technological and methodological advances – I hope to convince you that modern microbial biodiscovery has undergone (and continues to undergo) a renaissance, and is poised to re-imagine and re-inspire the future of drug discovery.