<p>This review delves into geomicrobial bioprospecting, which is an interdisciplinary, emerging field for the pursuit of novel bioactive compounds from microorganisms that thrive in extreme geologic environments. These sites, high-pressure deep-sea hydrothermal vents, hypersaline lakes, volcanic systems, polar cryoenvironments, and the deep subsurface biosphere, create intense geochemical stresses that have driven the evolution of unusual microbial metabolic pathways. A systematic tour of these frontiers underscores the link between specific environmental pressures and the biosynthesis of particular classes of molecules of interest, including new antibiotics, anticancer agents, cryoprotectants, and enzyme inhibitors. The review also covers the modern tools-triad of metagenomics, bioinformatics, and synthetic biology-for discovering and producing these compounds from practically unculturable microbial communities. Finally, the review attempts to situate the scientific endeavour in current legal and ethical frameworks, such as the Nagoya Protocol and the BBNJ Treaty, while also treating some of the ever-present problems of commercial-scale production. Geomicrobial bioprospecting is a logical, hypothesis-driven approach to replenishing our pharmacopoeia, the rich, basically untapped chemical diversity generated by the co-evolution of life and our planet.</p> Graphical Abstract <p></p>