Microbial metabolites are remarkable versatile as potent and selective drug lead candidates, and as in situ molecular probes, capable of interrogating key signalling, transport and developmental pathways. Microbial biodiscovery as a drug discovery paradigm has served science and society extremely well, and with appropriate modernisation and reinvestment is well placed to continue to do so into the future. Advances across many disciplines have revealed an untapped silent microbial secondary metabolism, which promises access to unprecedented bioactive chemical space. This renewed capacity can be further enhanced by recognition of the critical importance of widening the search parameters from narrow single bioassay/indication directed programs, to target both active and (seemingly) inactive metabolites, as well as new and known compounds, and a diversity of non-enzymatic chemical transformation products (all too often dismissed as artefacts). Many of the technical and commercial challenges that confronted microbial biodiscovery late last century have been resolved. The need is great and the time is right to re-plumb microbial biodiscovery back into the drug discovery pipeline.