Fungi have long been a prolific source of natural products that become FDA-approved medicines for bacterial infections, immune disorders, high blood pressure, and other conditions. Over 5 million fungal species, each with as many as 80 natural product biosynthetic pathways, are estimated to exist. But scientists can only culture a small fraction of fungi in the lab, and fungi don’t express all their biosynthetic gene clusters actively. In the past, researchers have produced several fungal natural products by engineering them into readily cultured microorganisms like yeast. Maureen E. Hillenmeyer and Colin J. B. Harvey of Stanford University School of Medicine and coworkers have now developed a more comprehensive fungal natural product discovery system (Sci. Adv. 2018, DOI: 10.1126/sciadv.aar5459). In this system, called HEx (heterologous expression), the researchers identify relevant gene clusters in fungal sequence databases, endow promising ones with high-producing promoters, engineer them into yeast, and collect and analyze the resulting natural products. When they applied HEx to 41 gene clusters, more than half produced detectable compounds (one example shown). “The finding that about half led to production of new metabolites in yeast is amazing and truly raises the possibility that novel, medically relevant compounds can be identified by exploiting a huge fungal gene pool that has so far been difficult to access,” says Uffe Mortensen of the Technical University of Denmark. Hexagon Bio, in Menlo Park, Calif., is commercializing HEx.